Self-eliminating coatings

ABSTRACT

The invention features the use of a matrix consisting of low molecular weight components for use as a self-eliminating coating for implantable medical devices. The matrix coatings can be used to enhance biocompatibility and to control the local delivery of biologically active agents.

BACKGROUND OF THE INVENTION

The invention relates to a coating for medical devices.

Implantable medical articles can be instrumental in saving and/orenhancing the quality of the life of patients. However, a significantbander to the use of implantable devices is the possibility of adversereactions of the body such as thrombogenic and immune responses. Commonmaterials used to manufacture implantable medical articles includemetals, minerals or ceramics, and polymers. It is generally desirable tomodify the surface of such materials in order to provide the surfacewith properties that are different from the properties of the material,e.g., in terms of infection resistance (i.e., via the delivery of abiologically active agent), thromboresistance, radiopacity,conductivity, and/or biocompatibility.

Various synthetic techniques have been used to impart desired chemical,physical and biological properties to materials used to manufactureimplantable medical devices. One approach, for example, involvesapplication of a parylene coating to devices, wherein a low molecularweight monomer is condensed and polymerized on a substrate, forming amatrix on the surface of the medical device. In another approach,biomaterials, e.g., heparin or albumin, are coupled directly to thesurface of the medical device to reduce thrombogenicity (Nicholas A.Peppas et al., Science, 263: 1715 (1994)). Such approaches have a numberof limitations. For example, a thick polymer coating, or asurface-coupled polymer coating, when applied to a medical device, suchas a stent, will often have different physical properties than theunderlying substrate (i.e., a metal) and, consequently, may not respondsimilarly to tensile, shear, or compression forces, causing the coatingto crack, flake, or delaminate. Such instability can have seriousadverse consequences when the coating cracks, flakes, or delaminates invivo. This problem is exacerbated for certain medical devices, such ascatheters and stents, which are subjected to deformation in vivo. Whenthe device expands, it is important that the coating is capable ofundergoing the same deformation without breaking or coming loose.

The safety of implantable devices can also be compromised by a lack ofbiocompatibility. Once implanted, a medical device resides in contactwith tissue and may produce local inflammation, at the site ofimplantation, as the host responds to the implant as a foreign body. Thedesign of a drug delivery platform that addresses the host's response toan implantable device has long been desired. Medical implants areexcellent platforms for direct and localized drug delivery, however thechallenge is with the polymer system used for such applications. Forexample, although cardiovascular stents revolutionized the management ofcontrolling the re-narrowing of artries, stent-restenosis persists as aclinical risk factor. To address this problem, at the molecular level, ahost of polymers as drug delivery platforms have been used. This wascaptured in the design and implantation of drug eluting stents. Howeverthe drug delivery platforms used in “drug eluting stents” are generallydurable polymers and remain on the stent platform for an indefinitetimeline which in turn initiates a series of un-desired host responses(Perin et al., Review in Cardiovascular Medicine, 6:S13 (2005)). Coatingof a pharmaceutically active compound directly on a stent platform hasalso been investigated. Crystallinity of the deposited pharmaceuticallyactive compound on the surface is often the result. The formation of acrystalline coating produces a dumping effect in which all of the drugon the stent is released at one time. Such a release profile isundesirable because it can result in toxicity leading to necrosis at thesite of release.

New coatings that can function as drug delivery matrices, are easy toapply, biocompatible, and have a limited residency time, while allowingfor the controlled release of biologically active agents, are needed toaddress the limitations present in the art.

SUMMARY OF THE INVENTION

The invention features the use of a matrix coating consisting of lowmolecular weight components and comprising an oligomer and abiologically active agent. The matrix coatings are self-eliminating orbioerodible upon implantation into a subject. The matrix coatings can beused to enhance biocompatibility and to control the local delivery ofbiologically active agents.

In a first aspect, the invention features an implantable medical devicehaving a surface and a matrix coating applied to the surface of theimplantable medical device, the matrix coating consisting of componentshaving a molecular weight of less than 20 kDa, the matrix coatingincluding (i) an oligomer and (ii) a biologically active agent, whereinthe matrix coating is self-eliminating or bioerodible upon implantationinto a subject and wherein the biologically active agent when on theimplantable medical device resides solely within the matrix coating.

In a related aspect, the invention features a method for making a coatedimplantable medical device having a surface by coating the surface witha matrix coating consisting of components having a molecular weight ofless than 20 kDa, the matrix coating including (i) an oligomer and (ii)a biologically active agent, wherein the matrix coating isself-eliminating or bioerodible upon implantation into a subject andwherein the biologically active agent when on the implantable medicaldevice resides solely within the matrix coating.

In certain embodiments, the matrix and the biologically active agent areapplied to the surface by spray coating, printing, or dip coating theimplantable medical device, or using any other application methodsdescribed herein.

The biologically active agents can be selected from proteins, peptides,carbohydrates, antibiotics, antiproliferative agents, rapamycinmacrolides, analgesics, anesthetics, antiangiogenic agents,antithrombotic agents, vasoactive agents, anticoagulants,immunomodulators, cytotoxic agents, antiviral agents, antibodies,neurotransmitters, psychoactive drugs, oligonucleotides, vitamins,lipids, prodrugs thereof. Biologically active agents useful in themethods and matrix coatings of the invention include any biologicallyactive agent described herein.

In certain embodiments, the biologically active agent is simply mixedwith oligomers of the matrix coating. In other embodiments, thebiologically active agent is covalently tethered to, or complexed to, anoligomer in the matrix coating.

In still other embodiments, the biologically active agent is uniformlydistributed throughout the matrix coating. For example, the biologicallyactive agent can be dissolved in the matrix coating.

In another aspect, the invention features an implantable medical devicehaving a surface and a matrix coating applied to the surface of theimplantable medical device, the matrix coating including anoligofluorinated oligomer, wherein the matrix coating isself-eliminating or bioerodible upon implantation into a subject andwherein the oligofluorinated oligomer when on the implantable medicaldevice resides solely within the matrix coating.

In a related aspect, the invention features a method for making a coatedimplantable medical device having a surface by coating the surface witha matrix coating including an oligofluorinated oligomer, wherein thematrix coating is self-eliminating or bioerodible upon implantation intoa subject and wherein the oligofluorinated oligomer when on theimplantable medical device resides solely within the matrix coating.

The implantable medical devices of the invention can have a surfacematerial selected from, for example, metals, metal alloys, ceramics,base polymers, and glasses. Implantable medical devices that can becoated using the methods and matrix coatings of the invention include,without limitation, cardiac-assist devices, catheters, stents,prosthetic implants, artificial sphincters, drug delivery devices, andany other implantable devices described herein. In certain embodiments,the implantable medical device is a stent.

The invention further features a stent having a surface and a matrixcoating applied to the surface of the stent, the matrix coatingconsisting of components having a molecular weight of less than 20 kDa,the matrix coating including (i) an oligomer and (ii) a biologicallyactive agent selected from antiproliferative agents and rapamycinmacrolides, wherein the matrix coating is self-eliminating orbioerodible upon implantation into a subject and wherein thebiologically active agent when on the stent resides solely within thematrix coating.

The invention also features a stent having a surface and a matrixcoating applied to the surface of the stent, the matrix coatingincluding an oligofluorinated oligomer, wherein the matrix coating isself-eliminating or bioerodible upon implantation into a subject andwherein the oligofluorinated oligomer when on the stent resides solelywithin the matrix coating. In certain embodiments, the matrix coatingfurther includes a biologically active agent selected fromantiproliferative agents and rapamycin macrolides.

Antiproliferative agents which can be used on the coated stents of theinvention include, without limitation, methotrexate, trimetrexate,gemcitabine, vinblastine, vincristine, etoposide, teniposide, topotecan,irinotecan, camptothecin, 9-aminocamptothecin, paclitaxel, docetaxel,daunorubicin, doxorubicin, dactinomycin, idarubincin, bleomycin,tamoxifen, and any other antiproliferative agent described herein.

Rapamycin macrolides which can be used on the coated stents of theinvention include, without limitation, rapamycin, CCI-779, Everolimus,ABT-578, and any other rapamycin macrolide described herein.

In a related aspect, the invention features a method for inhibitingrestenosis at a site in a vessel by implanting a stent of the inventionat the site.

The invention further features a method for delivering a biologicallyactive agent to a subject by implanting into the subject an implantablemedical device having a matrix coating of the invention, where thecoating matrix includes a biologically active agent.

Oligomers that can be used in the methods and matrix coatings of theinvention include polyurethanes, polyureas, polyamides, polyalkyleneoxides, polycarbonates, polyesters, polylactones, polysilicones,polyethersulfones, polyolefins, polyvinyls, polypeptides,polysaccharides, and combinations thereof.

In certain embodiments, an oligomer in the matrix coating is anoligofluorinated oligomer. The oligofluorinated oligomers can be anydescribed herein. In one embodiment, the oligofluorinated oligomer isdescribed by formula (I):

In formula (I), oligo is an oligomeric segment; Bio is a biologicallyactive agent; F_(T) is an oligofluoro group; each Link B is,independently, an organic moiety covalently bound to oligo, F_(T), orBio; a is an integer greater than 0; b and c are each, independently,integers greater than or equal to 0; and d is 0 or 1. In anotherembodiment, the oligofluorinated oligomer is described by formula (II):

F_(T)-[B-(oligo)]_(n)-B-(F_(T))_(g)  (II)

In formula (II), B includes a urethane; oligo includes polycarbonate,polypropylene oxide, polyethylene oxide, or polytetramethyleneoxide;F_(T) is an oligofluoro group; g is 0 or 1; and n is an integer from 1to 10.

Oligofluoro groups include, without limitation, groups having theformula:

CF₃(CF₂)_(p)X, (CF₃)₂CF(CF₂)_(p)X, or (CF₃)₃C(CF₂)_(p)X,

wherein X is CH₂CH₂—, (CH₂CH₂O)_(n), CH₂CH(OH)CH₂O—, CH₂CH(CH₂OH)O—, ora bond; p is an integer between 2 and 20; and n is an integer between 1and 10.

In any of the above methods and coatings of the invention, the matrixcoating can consist of components having a molecular weight of less than40 kDa, 35 kDa, 30 kDa, 25 kDa, 18 kDa, 16 kDa, 14 kDa, 12 kDa, 10 kDa,9 kDa, 8 kDa, 7 kDa, 6 kDa, 5 kDa, 4 kDa, or even 3 kDa.

The coatings of the invention can by applied by brushing, printing,spraying, wiping, or dipping the surface with the matrix coating. Incertain embodiments, the step of coating includes dissolving theconstituents of the matrix coating in a solvent to form a solution andapplying the solution to the surface of the implantable medical device.In still other embodiments, the step of coating includes mixing theconstituents of the matrix with a diluent to form a fluid mixture andapplying the fluid mixture to the surface of the implantable medicaldevice.

In any of the above methods and coatings of the invention, the matrixcoating can have a thickness of from 0.01 to 25 microns, 0.05 to 15microns, 0.1 to 25 microns, 0.1 to 15 microns, 0.1 to 10 microns, 0.1 to5 microns, 0.1 to 3 microns, or even 0.1 to 1 microns.

In any of the above methods and coatings of the invention, the uncoatedimplantable medical device is coated to produce a coated implantablemedical device, the coated implantable medical device having, uponimplantation into an animal, reduced protein deposition, reducedfibrinogene deposition, reduced platelet deposition, or reducedinflammatory cell adhesion in comparison to said uncoated implantablemedical device.

By “base polymer” is meant a self supporting polymer having a tensilestrength of from about 350 to about 10,000 psi, elongation at break fromabout 300% to about 1500%, an unsupported thickness of from about 5 toabout 100 microns, and a supported thickness of from about 1 to about100 microns.

As used herein, “LinkB” refers to a coupling segment capable ofcovalently linking oligomers, biologically active agents, and/oroligofluoro groups. Typically, LinkB molecules have molecular weightsranging from 40 to 700. Preferably the LinkB molecules are selected fromthe group of functionalized diamines, diisocyanates, disulfonic acids,dicarboxylic acids, diacid chlorides and dialdehydes, wherein thefunctionalized component has secondary functional chemistry that isaccessed for chemical attachment of an oligofluoro group. Such secondarygroups include, for example, esters, carboxylic acid salts, sulfonicacid salts, phosphonic acid salts, thiols, vinyls and secondary amines.Terminal hydroxyls, amines or carboxylic acids on the oligointermediates can react with diamines to form oligo-amides; react withdiisocyanates to form oligo-urethanes, oligo-ureas, oligo-amides; reactwith disulfonic acids to form oligo-sulfonates, oligo-sulfonamides;react with dicarboxylic acids to form oligo-esters, oligo-amides; reactwith diacid chlorides to form oligo-esters, oligo-amides; and react withdialdehydes to form oligo-acetal, oligo-imines.

By “oligo” or “oligomer” is meant a relatively short length of arepeating unit or units, generally less than about 50 monomeric unitsand molecular weights less than 10,000 but preferably <5,000 Daltons.Preferably, oligo is selected from the group consisting of polyurethane,polyurea, polyamides, polyalkylene oxide, polycarbonate, polyester,polylactone, polysilicone, polyethersulfone, polyolefin, polyvinyl,polypeptide, polysaccharide; and ether and amine linked segmentsthereof.

By “prodrug” is meant a precursor to a biologically active agent whichis converted in vivo, e.g., by enzymatic and/or hydrolytic mechanisms,into a biologically active agent. Prodrugs include, without limitation,esterified biologically active agents. Prodrugs useful in the methodsand compositions of the invention include, for example, biologicallyactive agents covalently tethered via a hydrolyzable linkage to anoligomer in a matrix coating of the invention.

As used herein, “self-eliminating” refers to the diffusion of a matrixcoating from the surface of an implantable medical device.Self-eliminating coatings are those in which greater than 70%, 80%, oreven 90% (w/w) of the coating diffuses from the surface over a period ofless than 2 months, 1 month, or 15 days under flow conditions in buffer,artificial urine, or plasma as provided in the Examples. It isunderstood that the self-elimination kinetics of any matrix coating onany particular implantable device will vary with the shape of thedevice, the constituents of the matrix, and the site of implantation. Ofimportance is that the matrix coatings of the invention are designed tobe transitory in nature, leaving the original uncoated implantablemedical device intact at the site of implantation.

As used herein, “bioerodible” refers to the diffusion of a matrixcoating from the surface of an implantable medical device. Bioerodiblecoatings are those in which greater than 30%, 40%, or 50% (w/w) of thecoating diffuses from the surface over a period of less than 6 months, 4months, 3 months, 2 months, or 1 month under sink conditions in buffer,artificial urine, or plasma as provided in the Examples. It isunderstood that the self-elimination kinetics of any matrix coating onany particular implantable device will vary with the shape of thedevice, the constituents of the matrix, and the site of implantation. Ofimportance is that the matrix coatings of the invention are designed tobe transitory in nature, leaving the original uncoated implantablemedical device intact at the site of implantation.

As used herein, “covalently tethered” refers to moieties separated byone or more covalent bonds. For example, where an oligofluoro group iscovalently tethered to an oligomer, tethered includes the moietiesseparated by a single bond as well as both moieties separated by, forexample, a LinkB segment to which both moieties are covalently attached.

As used herein, the term “oligofluorinated” refers to an oligomercovalently linked to an oligofluoro group for use in a matrix coating ofthe invention.

As used herein, “complexed” or “complexation” refers to an interaction,either non-covalent or via coordination to a metal center, between acomplexing moiety in an oligomer contained within a matrix coating ofthe invention and a biologically active agent. Examples of non-covalentbonding interactions which can be used in accordance with the presentinvention include, without limitation, hydrogen bonding, ionicinteractions (e.g., dipole-dipole interactions, ion pairing, and saltformation), inclusion complexes, clathration, van der Waals interactions(e.g., pi-pi stacking), and combinations thereof. The interaction canalso be via coordination to a metal center by both the complexing moietyand the biologically active agent. In some instances, the biologicallyactive agent includes a metal center which is coordinated to thecomplexing moiety.

As used herein, “complexing moiety′ refers to certain embodiments of theinvention including a portion of an oligomer contained within a matrixcoating of the invention which complexes a biologically active agenteither via a non-covalent interaction or coordination to a metal center,forming a polymer complex. The complexing moiety can be a chargedmoiety, e.g., a moiety which loses a proton at physiological pH therebybecoming negatively charged (e.g., carboxylate, or phosphodiester), amoiety which gains a proton at physiological pH thereby becomingpositively charged (e.g., ammonium, guanidinium, or amidinium), a moietythat includes a net formal positive charge without protonation (e.g.,quaternary ammonium), or a moiety that includes a net formal negativecharge without loss of a proton (e.g., borate, BR₄ ⁻). Exemplary chargedcomplexing moieties include, without limitation, carboxylate,phosphodiester, phosphoramidate, borate, phosphate, phosphonate,phosphonate ester, sulfonate, sulfate, thiolate, phenolate, ammonium,amidinium, guanidinium, quaternary ammonium, and imidazoliumfunctionalities. The complexing moiety can be designed to physicallyencapsulate, in whole or in part, the biologically active agent, such asa cyclodextrin. The complexing moiety be designed to ligate acomplementary oligonucleotide and/or peptide sequence present in thebiologically active agent. The complexing moiety can be designed tocoordinate a metal center including the biologically active agent,either as a ligand alone or including the metal center.

A description of how make complexing moieties and complexation withbiologically active agents is described in U.S. Patent Publication No.20070037891, incorporated herein by reference.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description, the Drawings, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a 3D HPLC chromatogram of Compound 3, showing a pure materialwith no side products.

FIG. 2 is an SEM image of a stent coated with Compound 1, showing thincoverage with minimal webbing.

FIG. 3 is an SEM image of a stent coated with Compound 1, crimped anddeployed in buffer, showing thin coverage.

FIG. 4 is an SEM image of a stent coated with Compound 2, showing thincoverage with minimal webbing.

FIG. 5 is a confocal/fluorescent microscopy (5× Fluor lens and a DAPI UVfilter) image of a stent coated with Compound 3, indicating the presenceof Compound 3 on the stent surface.

FIG. 6 is a confocal/fluorescent microscopy (5× Fluor lens and a DAPI UVfilter) image of a crimped stent coated with Compound 3, indicating thepresence of Compound 3 on the stent surface.

FIG. 7 is a confocal/fluorescent microscopy (5× Fluor lens and a DAPI UVfilter) image of a deployed stent coated with Compound 3, indicating thepresence of Compound 3 on the stent surface.

FIG. 8 is an SEM image of a stent coated with Compound 4, indicating athin coating.

FIG. 9 is an SEM image of a stent coated with Compound 5, indicating athin coating.

FIG. 10 is an SEM image of a stent coated with Compound 6, indicating athin coating.

FIG. 11 is an SEM image of a stent coated with Compound 7, indicating athin coating.

FIG. 12 is an SEM image of a stent coated with Compound 8, indicating athin coating.

FIG. 13 is an SEM image of a stent coated with Compound 9, indicating athin coating.

FIG. 14 is an SEM image of a stent coated with Compound 10, indicating athin coating.

FIG. 15 is an SEM image of a stent coated with Compound 11, indicating athin coating.

FIG. 16 is an SEM image of a stent coated with Compound 12, indicating athin coating.

FIG. 17 is an SEM image of a stent coated with Compound 14, indicating athin coating.

FIG. 18 is an SEM image of a stent coated with Compound 15, indicating athin coating.

FIG. 19 is an SEM image of a stent coated with Compound 1 and Compound7, indicating a thin coating.

FIG. 20 is an SEM image of a stent coated with Compound 2+8.8 wt % PTX,indicating a thin coating.

FIG. 21 is an SEM image of a stent coated with Compound 6+8.8 wt % PTX,indicating a thin coating.

FIG. 22 is a plot of PTX release from Compound 1, 2, and 6+5, 8.8 and 20wt % PTX into Tween PBS at 37° C. (films cast in vials), showing theeffect of Compound and PTX concentration on release.

FIG. 23 is a plot of PTX release from Compound 1 and 6+5 and 8.8 wt %PTX into Tween PBS at 20° C. (films cast in vials), showing effect ofCompound and PTX concentration on release.

FIG. 24 is a plot of PTX release from Compound 1 and 6+5 and 8.8 wt %PTX into Tween PBS at 37° C. (films cast in vials), showing effect ofCompound and PTX concentration on release.

FIG. 25 is an SEM image of a stent coated with Compound 1+8.8 wt % PTX,showing good coverage.

FIG. 26 is a series of SEM images of Compounds+1 wt % PTX coated onstents, showing good coverage: (a) Compound 1, (b) Compound 6, (c)Compound 7, (d) Compound 1+7, (e) Compound 8, (f) Compound 9, (g)Compound 12.

FIG. 27 is a picture of a Compound 1+8.8 wt % PTX coated coupon securedto cardiac muscle, showing contact between the two substrates.

FIG. 28 is a picture of a coupon coated with Compound 1+8.8 wt % PTXafter contact with cardiac muscle, showing the appearance of thecoating.

FIG. 29 is a plot of PTX remaining on the stainless steel coupons coatedwith Compound 1+8.8% PTX in contact with cardiac muscle, showing the PTXrelease profile.

FIG. 30 is a plot of PTX remaining on the stainless steel coupons coatedwith Compound 1+1% PTX in contact with cardiac muscle, showing the PTXrelease profile.

FIG. 31 is a plot of the residency of Compounds 1, 2, 3, 6, 7, 1+7, 8,9, 10, 11, 12, 14, 15, and 16 in a PBS sink condition, showing theeffect of formulation on residency time.

FIG. 32 is a plot of the residency of Compounds 1, 2, 6, 7, 1+7, 10, and12 on stainless steel coupons under sink condition in PBS, showing theeffect of formulation on residency time.

FIG. 33 is a plot of the residency of Compounds 1, 2, 6, 7, 1+7, 10, and12 (vials) in a porcine blood sink condition, showing the effect offormulation on residency time.

FIG. 34 is a plot of the residency of Compounds 1, 2, 10, and 12 onstainless steel coupons under sink condition in porcine blood, showingthe effect of formulation on residency time.

FIG. 35 is a plot of the residency of Compounds 1, 2, 6, 7, 1+7, 10 and12 in artificial urine sink condition, showing the effect of formulationon residency time.

FIG. 36 is a plot of the residency of Compounds 1, 2, 4, and 6 in PBSflow condition, showing the effect of formulation on residency time.

FIG. 37 is a plot of the residency of Compounds 1, 2 and 6 in porcineblood, flow condition, showing the effect of formulation on residencytime.

FIG. 38 is a plot of the residency of Compounds 1, 2, and 6 inartificial urine, flow condition, showing the effect of formulation onresidency time.

FIG. 39 is a picture of the porcine hearts used for the residency timestudy of Compounds 1, 2, 4 and 6. The image shows incision size andposition.

FIG. 40 is a plot of a long term residency study of Compounds 1, 2, 3,6, 7, 1+7, 8, 9, 10, 11, 12, 14, 15, and 16 in PBS sink condition,showing the ability to fine-tune the delivery time.

FIG. 41 is a plot of mass loss for Compounds 1, 5, 7, and DL-PLGA afterincubation in various solutions, showing the effect of media.

FIG. 42 contains SEM images of stainless steel coupons coated with (a)Compound 1, (b) Compound 6, (c) Compound 7, (d) Compound 1+7, (e)Compound 8, (f) Compound 9, (g) Compound 10, (h) Compound 11, (i)Compound 12, (j) Compound 14 and (k) Compound 15, showing smoothcoverage.

FIG. 43 contains pictures of coated stainless steel coupons before andafter contact with porcine blood, showing no appreciable changes to thecoatings: (a) Compound 1, (b) Compound 6, (c) Compound 7, (d) Compound1+7, (e) Compound 8, (f) Compound 9, (g) Compound 10, (h) Compound 11,(i) Compound 12, (j) Compound 14 and (k) Compound 15.

FIG. 44 is a plot of U937 cell interaction with Compounds 1, 2, 6, 7,1+7, 8, 9, 10, 11, 12, 15 and 16, showing the ability to minimizemacrophage adhesion.

FIG. 45 is a plot of HCAEC migration through membranes coated withCompound 1, Compound 1+PTX, and SIBS, demonstrating good migration ofHCAEC through membranes coated with Compound 1.

FIG. 46 is a plot of platelet and fibrinogen interactions with sprayedfilms of Compounds 1, 7, 1+7 and 12, showing reduction in plateletadhesion and fibrinogen adsorption.

FIG. 47 contains histology images of vessel cross-sections from twoanimals (A and B), showing biocompatibility profile.

FIG. 48 contains SEM images of a stent coated with Compound 3 at day 0(left) and day 42 (right), showing the stability of the coatings instorage.

FIG. 49 contains SEM images of stents coated with Compound 3 after 24hours (left) and 7 days (right) exposure to porcine blood, showing thecoating profile.

FIG. 50 is an image of a Compound 3 coated stent explanted from aporcine LCX artery, showing contact between the vessel wall and thestent.

DETAILED DESCRIPTION

The methods and compositions of the invention feature a matrix coatingconsisting of low molecular weight components and comprising (i) anoligomer and a biologically active agent, or (ii) an oligofluorinatedoligomer. The matrix coatings are self-eliminating or bioerodible uponimplantation into a subject. The matrix coatings can be used to enhancebiocompatibility and to control the local delivery of biologicallyactive agents.

Oligomers

The matrix coating of the invention includes an oligomer. Oligomerswhich can be used in the matrix coatings of the invention include,without limitation, polyurethanes, polyureas, polyamides, polyaklyleneoxides, polycarbonates, polyesters, polylactones, polysilicones,polyethersulfones, polyolefins, polyvinyl derivatives, polypeptides,polysaccharides, polysiloxanes, polydimethylsiloxanes,polyethylene-butylene, polyisobutylenes, polybutadienes, polypropyleneoxides, polyethylene oxides, polytetramethyleneoxides,polyethylenebutylenes, polycaprolactone, polylactic, polyethyleneglycol, polypropylene glycol, polydiethyleneglycol phthalate,polydiethyleneglycol adipate, polyhydroxybutyrate, polyhydroxyoctanoate,polyhydroxyvalerate, biOH™ soybean oil-derivative (Cargill), andcombinations and mixtures thereof.

The matrix coating may optionally contain an oligomer complexed, orcovalently tethered, to a biologically active agent, or applied in amixture including a biologically active agent.

The amount of biologically active agent loaded into the coating willdepend upon the design of the oligomer in combination with the desiredrelease profile. The oligomer may be designed for the particular agentbeing delivered and to provide the biocompatibility necessary for aparticular application.

The process by which the polymer complex is formed may be a two ormulti-step procedure. In general, oligofluorinated oligomers used in themethods and compositions of the invention can be prepared as describedin U.S. Pat. No. 6,127,507, and U.S. Ser. No. 11/404,290, each of whichis incorporated herein by reference.

Biologically Active Agents

Biologically active agents can be incorporated in the coatings of theinvention. The incorporation can be achieved either by mixing the matrixcoating components and the biologically active agent together andapplying the mixture to the surface of the article prior toimplantation. In some instances, the biologically active agent iscovalently tethered or complexed to an oligomer in the matrix coating. Adetailed description of how biologically active agents may be covalentlytethered or complexed to an oligofluorinated oligomeris provided in U.S.Pat. No. 6,770,725 and U.S. Ser. No. 11/404,290, each of which isincorporated herein by reference. Biologically active agents that can beused in the methods and compositions of the invention includetherapeutic, diagnostic, and prophylactic agents. They can be naturallyoccurring compounds, synthetic organic compounds, or inorganiccompounds. Biologically active agents that can be used in the methodsand compositions of the invention include, but are not limited to,proteins, peptides, carbohydrates, antibiotics, antiproliferativeagents, rapamycin macrolides, analgesics, anesthetics, antiangiogenicagents, vasoactive agents, anticoagulants, immunomodulators, cytotoxicagents, antiviral agents, antithrombotic drugs, such as terbrogrel andramatroban, antibodies, neurotransmitters, psychoactive drugs,oligonucleotides, proteins, lipids, and any biologically active agentdescribed herein.

Exemplary therapeutic agents include growth hormone, for example humangrowth hormone, calcitonin, granulocyte macrophage colony stimulatingfactor (GMCSF), ciliary neurotrophic factor, and parathyroid hormone.Other specific therapeutic agents include parathyroid hormone-relatedpeptide, somatostatin, testosterone, progesterone, estradiol, nicotine,fentanyl, norethisterone, clonidine, scopolomine, salicylate,salmeterol, formeterol, albeterol, valium, heparin, dermatan,ferrochrome A, erythropoetins, diethylstilbestrol, lupron, estrogenestradiol, androgen halotestin, 6-thioguanine, 6-mercaptopurine,zolodex, taxol, lisinopril/zestril, streptokinase, aminobutytric acid,hemostatic aminocaproic acid, parlodel, tacrine, potaba, adipex,memboral, phenobarbital, insulin, gamma globulin, azathioprine, papein,acetaminophen, ibuprofen, acetylsalicylic acid, epinephrine,flucloronide, oxycodone percoset, dalgan, phreniline butabital,procaine, novocain, morphine, oxycodone, aloxiprin, brofenac,ketoprofen, ketorolac, hemin, vitamin B-12, folic acid, magnesium salts,vitamine D, vitamin C, vitamin E, vitamin A, Vitamin U, vitamin L,vitamin K, pantothenic acid, aminophenylbutyric acid, penicillin,acyclovir, oflaxacin, amoxicillin, tobramycin, retrovior, epivir,nevirapine, gentamycin, duracef, ablecet, butoxycaine, benoxinate,tropenzile, diponium salts, butaverine, apoatropine, feclemine,leiopyrrole, octamylamine, oxybutynin, albuterol, metaproterenol,beclomethasone dipropionate, triamcinolone acetamide, budesonideacetonide, ipratropium bromide, flunisolide, cromolyn sodium, ergotaminetartrate, and protein or peptide drugs such as TNF antagonists orinterleukin antagonists. For example, the biologically active agent canbe an antiinflammatory agent, such as an NSAID, corticosteriod, or COX-2inhibitor, e.g., rofecoxib, celecoxib, valdecoxib, or lumiracoxib.

Exemplary diagnostic agents include imaging agents, such as those thatare used in positron emission tomography (PET), computer assistedtomography (CAT), single photon emission computerized tomography, X-ray,fluoroscopy, and magnetic resonance imaging (MRI). Suitable materialsfor use as contrast agents in MRI include gadolinium chelates, as wellas iron, magnesium, manganese, copper, and chromium chelates. Examplesof materials useful for CAT and X-rays include iodine based materials.

A preferred biologically active agent is a substantially purifiedpeptide or protein. Proteins are generally defined as consisting of 100amino acid residues or more; peptides are less than 100 amino acidresidues. Unless otherwise stated, the term protein, as used herein,refers to both proteins and peptides. The proteins may be produced, forexample, by isolation from natural sources, recombinantly, or throughpeptide synthesis. Examples include growth hormones, such as humangrowth hormone and bovine growth hormone; enzymes, such as DNase,proteases, urate oxidase, alronidase, alpha galactosidase, and alphaglucosidase; antibodies, such as trastuzumab.

Rapamycin Macrolides

Rapamycin (Sirolimus) is an immunosuppressive lactam macrolide that isproduced by Streptomyces hygroscopicus. See, for example, McAlpine, J.B., et al., J. Antibiotics 44: 688 (1991); Schreiber, S. L., et al., J.Am. Chem. Soc. 113: 7433 (1991); and U.S. Pat. No. 3,929,992,incorporated herein by reference. Exemplary rapamycin macrolides whichcan be used in the methods and compositions of the invention include,without limitation, rapamycin, CCI-779, Everolimus (also known asRAD001), and ABT-578. CCI-779 is an ester of rapamycin (42-ester with3-hydroxy-2-hydroxymethyl-2-methylpropionic acid), disclosed in U.S.Pat. No. 5,362,718. Everolimus is an alkylated rapamycin(40-O-(2-hydroxyethyl)-rapamycin, disclosed in U.S. Pat. No. 5,665,772.

Antiproliferative Agents

Exemplary antiproliferative agents which can be used in the methods andcompositions of the invention include, without limitation,mechlorethamine, cyclophosphamide, iosfamide, melphalan, chlorambucil,uracil mustard, estramustine, mitomycin C, AZQ, thiotepa, busulfan,hepsulfam, carmustine, lomustine, semustine, streptozocin, dacarbazine,cisplatin, carboplatin, procarbazine, methotrexate, trimetrexate,fluouracil, floxuridine, cytarabine, fludarabine, capecitabine,azacitidine, thioguanine, mercaptopurine, allopurine, cladribine,gemcitabine, pentostatin, vinblastine, vincristine, etoposide,teniposide, topotecan, irinotecan, camptothecin, 9-aminocamptothecin,paclitaxel, docetaxel, daunorubicin, doxorubicin, dactinomycin,idarubincin, plicamycin, mitomycin, amsacrine, bleomycin,aminoglutethimide, anastrozole, finasteride, ketoconazole, tamoxifen,flutamide, leuprolide, goserelin, Gleevec™ (Novartis), leflunomide(Pharmacia), SU5416 (Pharmacia), SU6668 (Pharmacia), PTK787 (Novartis),Iressa™ (AstraZeneca), Tarceva™, (Oncogene Science), trastuzumab(Genentech), Erbitux™ (ImClone), PKI166 (Novartis), GW2016(GlaxoSmithKline), EKB-509 (Wyeth), EKB-569 (Wyeth), MDX-H210 (Medarex),2C4 (Genentech), MDX-447 (Medarex), ABX-EGF (Abgenix), CI-1033 (Pfizer),Avastin™ (Genentech), IMC-1C11 (ImClone), ZD4190 (AstraZeneca), ZD6474(AstraZeneca), CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518(Millenium), PKC412 (Novartis), 13-cis-retinoic acid, isotretinoin,retinyl palmitate, 4-(hydroxycarbophenyl) retinamide, misonidazole,nitracrine, mitoxantrone, hydroxyurea, L-asparaginase, interferon alfa,AP23573, Cerivastatin, Troglitazone, CRx-026DHA-paclitaxel, Taxoprexin,TPI-287, Sphingosine-based lipids, and mitotane.

Corticosteroids

Exemplary corticosteroids which can be used in the methods andcompositions of the invention include, without limitation,21-acetoxypregnenolone, alclomerasone, algestone, amcinonide,beclomethasone, betamethasone, betamethasone valerate, budesonide,chloroprednisone, clobetasol, clobetasol propionate, clobetasone,clobetasone butyrate, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacon, desonide, desoximerasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flumethasone pivalate,flunisolide, flucinolone acetonide, fluocinonide, fluorocinoloneacetonide, fluocortin butyl, fluocortolone, fluorocortolone hexanoate,diflucortolone valerate, fluorometholone, fluperolone acetate,fluprednidene acetate, fluprednisolone, flurandenolide, formocortal,halcinonide, halometasone, halopredone acetate, hydrocortamate,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone phosphate, hydrocortisone 21-sodium succinate,hydrocortisone tebutate, mazipredone, medrysone, meprednisone,methylprednicolone, mometasone furoate, paramethasone, prednicarbate,prednisolone, prednisolone 21-diedryaminoacetate, prednisolone sodiumphosphate, prednisolone sodium succinate, prednisolone sodium21-m-sulfobenzoate, prednisolone sodium 21-stearoglycolate, prednisolonetebutate, prednisolone 21-trimethylacetate, prednisone, prednival,prednylidene, prednylidene 21-diethylaminoacetate, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide andtriamcinolone hexacetonide. Structurally related corticosteroids havingsimilar anti-inflammatory properties are also intended to be encompassedby this group.

NSAIDs

Exemplary non-steroidal antiinflammatory drugs (NSAIDs) which can beused in the methods and compositions of the invention include, withoutlimitation, naproxen sodium, diclofenac sodium, diclofenac potassium,aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen,nabumetone, choline magnesium trisalicylate, sodium salicylate,salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen,meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin.

Analgesics

Exemplary analgesics which can be used in the methods and compositionsof the invention include, without limitation, morphine, codeine, heroin,ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone,hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine,metopon, ethorphine, acetorphine, diprenorphine, buprenorphine,phenomorphan, levorphanol, ethoheptazine, ketobemidone, dihydroetorphineand dihydroacetorphine.

Antimicrobials

Exemplary antimicrobials which can be used in the methods andcompositions of the invention include, without limitation, penicillin G,penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin,nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin,mezlocillin, piperacillin, azlocillin, temocillin, cepalothin,cephapirin, cephradine, cephaloridine, cefazolin, cefamandole,cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin,cefmatozole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone,ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome,cefepime, BAL5788, BAL9141, imipenem, ertapenem, meropenem, astreonam,clavulanate, sulbactam, tazobactam, streptomycin, neomycin, kanamycin,paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,sisomicin, dibekalin, isepamicin, tetracycline, chlortetracycline,demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline,erythromycin, azithromycin, clarithromycin, telithromycin, ABT-773,lincomycin, clindamycin, vancomycin, oritavancin, dalbavancin,teicoplanin, quinupristin and dalfopristin, sulphanilamide,para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole,sulfathalidine, linezolid, nalidixic acid, oxolinic acid, norfloxacin,perfloxacin, enoxacin, ofloxacin, ciprofloxacin, temafloxacin,lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin,clinafloxacin, gatifloxacin, moxifloxacin, gemifloxacin, sitafloxacin,metronidazole, daptomycin, garenoxacin, ramoplanin, faropenem,polymyxin, tigecycline, AZD2563, and trimethoprim.

Local Anesthetics

Exemplary local anesthetics which can be used in the methods andcompositions of the invention include, without limitation, cocaine,procaine, lidocaine, prilocaine, mepivicaine, bupivicaine, articaine,tetracaine, chloroprocaine, etidocaine, and ropavacaine.

Antispasmodic

Exemplary antispasmodics which can be used in the methods andcompositions of the invention include, without limitation, atropine,belladonna, bentyl, cystospaz, detrol (tolterodine), dicyclomine,ditropan, donnatol, donnazyme, fasudil, flexeril, glycopyrrolate,homatropine, hyoscyamine, levsin, levsinex, librax, malcotran, novartin,oxyphencyclimine, oxybutynin, pamine, tolterodine, tiquizium, prozapine,and pinaverium.

Matrix Coating

The matrix coatings of the invention can be designed to vary in adhesionto a surface by varying the size of oligomers, their solubility inphysiological media, and/or employing oligomers which favorably interactwith the surface on which the coating is placed. Such favorableinteractions can include, for example, coordination (i.e., carboxylategroups coordinating to a metal surface), and/or hydrogen bonding betweenthe oligomers and the device surface. In certain embodiments, the matrixcoating is applied to the surface of the implantable medical device toform a thin coating (i.e., 0.5-5.0 microns in thickness). Because thematrix coatings of the invention do not have the properties of a basepolymer, they are not susceptible to flaking or cracking during thephysical manipulation of the device, such as the crimping and deploymentof a stent. The matrix coatings of the invention control the release ofbiologically active agents incorporated within the matrix by limitingthe rate of diffusion of the agent from the matrix. The modified releaseprofile is achieved despite the low molecular weight of the matrixcomponent and the self-eliminating or bioerodible nature of the coating.

A primary function of such coating can be to locally deliver abiologically active agent for a defined period of time and leave thedevice surface intact once the therapy period is completed. The matrixcoating is optionally complexed, or covalently tethered, or physicallycombined with a biologically active agent, or applied in a mixtureincluding a biologically active agent. The amount of biologically activeagent loaded into the matrix coating will depend upon the desired localconcentration and release profile from the matrix coating.

The matrix coating of the invention is significantly different frombiodegradable and bioabsorbable polymers as the oligomers of the matrixremain intact during elimination from the surface of the device. Incertain embodiments, a biologically active agent is covalently bound toan oligomer in the matrix via a hydrolyzable linker. In theseembodiments, it is understood that the hydrolysis of the linker canoccur either within the matrix or after diffusion of the biologicallyactive agent from the surface of the device. It is desirable to limithydrolytic degradation near the site of implantation to avoid localizedchanges in pH and the generation of inflammatory side products.

The matrix coatings of the invention can be applied to the surface of amedical device in any number of ways including, but not limited, todipping, spraying, brushing, printing, or spin coating of the matrixcoating material from a solution or suspension followed by solventremoval step as needed. Further description of how the matrix coatingscan be applied is found in the Examples.

Coated Medical Devices

A wide variety of implantable medical devices can be coated using thecompositions and methods of the invention. Implantable medical devicescan be coated to improve their biocompatibility and to deliverbiologically active agents at the site of implantation. The medicaldevices include, without limitation, catheters, guide wires, vascularstents, micro-particles, probes, sensors, drug depots, transdermalpatches, vascular patches, and tubing. The medical device can be animplanted device, percutaneous device, or cutaneous device. Implanteddevices include articles that are fully implanted in a patient, i.e.,are completely internal. Percutaneous devices include items thatpenetrate the skin, thereby extending from outside the body into thebody. Cutaneous devices are used superficially. Implanted devicesinclude, without limitation, prostheses such as pacemakers, electricalleads such as pacing leads, defibrillators, artificial hearts,ventricular assist devices, anatomical reconstruction prostheses such asbreast implants, artificial heart valves, heart valve stents,pericardial patches, surgical patches, coronary stents, vascular grafts,vascular and structural stents, vascular or cardiovascular shunts,biological conduits, pledges, sutures, annuloplasty rings, stents,staples, valved grafts, dermal grafts for wound healing, orthopedicspinal implants, orthopedic pins, intrauterine devices, urinary stents,maxial facial reconstruction plating, dental implants, intraocularlenses, clips, sternal wires, bone, skin, ligaments, tendons, andcombination thereof. Percutaneous devices include, without limitation,catheters or various types, cannulas, drainage tubes such as chesttubes, surgical instruments such as forceps, retractors, needles, andcatheter cuffs. Cutaneous devices include, without limitation, burndressings, wound dressings and dental hardware, such as bridge supportsand bracing components.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

Acronyms

The following acronyms denote the listed compounds.

ACD acid citrate dextroseBAL poly(difluoromethylene),α-fluoro-ω-(2-hydroxyethyl)BPH neopentyl glycol phthalic anhydride based polyester diolCDCl₃ deuterated chloroformDBDL dibutyltin dilaurateDCM dichloromethaneDIC diisopropylcarbodiimideDL-PLGA DL-polylactic-co-glycolic acid polymerDMAc dimethylacetamideDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethylsuiphoxideEtO ethylene oxideHCAEC human coronary artery endothelial cellsHCl hydrochloric acidHLB hydroxy terminated polybutadieneHPCN hexamethylene polycarbonate diolKBr potassium bromideKD dansyl labelled lysineLDI lysine diisocyanateMeOH methanolNaOH sodium hydroxideExamN₂ nitrogen gasOPCN methyl polycarbonate diolPBS phosphate buffer solutionPCAEC porcine coronary artery endothelial cellsPEB polyethylene-co-butadiene diolPET polyethylene terephthalatePCL polycaprolactonePTT partial thromboplastin timePTMO polytetramethylene oxidePTX paclitaxelRBC red blood cellSA salicylic acidTEA triethylamineTHF tetrahydrofuranTMX m-tetramethylxylene diisocyanateTween PBS 0.05% Tween 20 in phosphate buffer solution

General Experimental Protocols

Cationic Solid Phase Extraction (SCX-SPE): A pre-packed cationic silicagel column (plastic) is used to remove small cationic compounds from thereaction mixtures.

Fluorous Solid Phase Extraction (F-SPE): SPE substrates modified withperfluorinated ligands (F-SPE) are used to selectively retainperfluorinated oligomers, allowing the separation of non-fluorinatedcompounds.

Elemental analysis: samples are combusted, and the liberated fluorine isabsorbed into water and analyzed by ion-selective electrode.

FTIR analysis: a sample is dissolved as a 20 mg/mL solution in asuitable volatile solvent and 50 μL of this solution is cast on a KBrdisk. Once dried, the sample is analyzed.

GPC analysis: samples are dissolved as a 20 mg/mL solution in a suitablesolvent (THF, dioxane, DMF) and are analyzed using a polystyrene columncalibrated with polystyrene standards.

NMR: samples are dissolved at 20 mg/mL in a suitable solvent and areanalyzed using a 300 or 400 MHz NMR spectrometer.

SEM: surfaces are coated with gold and images taken with an acceleratingvoltage of 20 kV.

XPS analysis: films are analyzed using a 90° take-off angle.

Oligomers: fluorinated and non fluorinated oligomers of differentchemical compositions are made to evaluate their coating, residency timeand compatibility with pharmaceutical compounds.

Pharmaceuticals: these compounds are selected according to mode ofcellular interactions and functional groups available for interactionswith drug delivery matrix.

Coating: coating methods are developed to demonstrate and establish thincoating of oligomers.

Residency time: flow and sink conditions (artificial urine, porcineblood, bovine blood, porcine plasma and cardiac muscle) are used tomeasure residency time

Example 1: Synthesis and Characterization of Compound 1(Oligofluoro-Ester)

PTMO (15.0 g, 14 mmol) was reacted with LDI (5.9 g, 28 mmol) in DMAc (80mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (13.15 g, 31 mmol) was dissolved in DMAc (25 mL), addedto the reaction, and stirred at room temperature overnight under N₂. Theproduct (Compound 1) was purified by solvent extraction and cationicSPE. GPC (dioxane mobile phase): retention time of 25 minutes. ¹H NMR(400 MHz, CDCl₃) δ (ppm) 4.24-4.46 (—CH₂—O, BAL), 3.94-4.13 (—CH₂—O—CO,PTMO), 3.74 (CH₃, LDI), 3.28-3.50 (CH₂—O, PTMO), 2.98-3.28 (CH₂ —NH,LDI), 2.29-2.60 (—CH₂—CF₂—, BAL), 1.16-1.96 (PTMO and LDI CH₂). IRanalysis was in accordance with the chemical structure: 3318 cm⁻¹ ν(N—H) H-bonded, 2930 cm⁻¹ ν (C—H), 2848 cm⁻¹ ν (C—H), 1712 cm⁻¹ ν (C═O)urethane amide, 1524 cm⁻¹ ν (C—N), 1438 cm⁻¹ ν (C—N), 1356 cm⁻¹ ν (C—O),1400-1000

cm⁻¹ ν (C—F). Elemental analysis: 20% F. DSC analysis: T_(g)=−69° C.Compound 1 was further purified by dissolving in MeOH and dialyzing forthree days using 1000 MWCO regenerated cellulose membranes (Compound1-D).

Example 2: Synthesis and Characterization of Compound 2(Oligofluoro-Acid)

Compound 1 was dissolved in MeOH and treated with 1N NaOH. The product(Compound 2) was neutralized with 1N HCl, precipitated in water, anddried. GPC (dioxane mobile phase): retention time of 25 minutes. ¹H NMR(400 MHz, CDCl₃) (ppm) 4.26-4.48 (—CH₂—O, BAL), 3.96-4.23 (—CH₂—O—CO,PTMO), 3.30-3.52 (CH₂—O, PTMO), 3.07-3.22 (CH₂ —NH, LDI), 2.36-2.55(—CH₂—CF₂—, BAL), 1.14-1.94 (PTMO and LDI CH₂). IR analysis was inaccordance with the chemical structure: 3318 cm⁻¹ ν (N—H) H-bonded, 2930

cm⁻¹ ν (C—H), 2848 cm⁻¹ ν (C—H), 1712 cm⁻¹ ν (C═O) urethane amide, 1524cm⁻¹ ν (C—N), 1438 cm⁻¹ ν (C—N), 1356 cm⁻¹ ν (C—O), 1400-1000 cm⁻¹ ν(C—F). Compound 2 was further purified by dissolving in MeOH anddialyzing for three days using 1000 MWCO regenerated cellulose membranes(Compound 2-D).

Example 3: Synthesis and Characterization of Compound 3(Oligofluoro-Dansyl, Covalent Conjugation)

Compound 2-D (2.0 g, 1.71 mmol acid) was dissolved in anhydrous DMF (25mL). The solution was chilled, DIC (0.215 g, 1.71 mmol) was added andthe solution was stirred for 2 hours at room temperature under N₂. TEA(0.345 g, 3.41 mmol) and dansyl-labelled lysine (KD) (0.718 g, 1.71mmol) in anhydrous DMF (9 mL) were added to the activated Compound 2-D,and the solution was kept well stirred for 12 hours at room temperatureunder N₂. The product (Compound 3) was purified with cationic andfluorous SPE, and recovered by rotary evaporation. GPC (dioxane mobilephase): no free KD was detected, and the polymer peak had strong UVabsorbance. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.14-8.59 (aromatic H, KD)4.46-4.66 (CH₂—N, KD), 4.28-4.48 (—CH₂—O, BAL), 3.90-4.17 (—CH₂—O—CO,PTMO), 3.31-3.54 (CH₂—O, PTMO), 3.06-3.26 (—CH₂ —NH, LDI), 2.81-3.00(CH₃, KD) 2.32-2.58 (—CH₂—CF₂—, BAL), 1.08-1.94 (CH₂, PTMO, LDI and KD).High performance liquid chromatography (HPLC) analysis of Compound 3:samples ranging in concentration from 0.0005 to 50 mg/mL in MeOH wereinjected and analyzed using an MeOH/pH 9 buffer mobile phase. Free KD(standard solution) eluted at 21 minutes, and Compound 3 eluted at 35minutes with no evidence of free KD contamination (FIG. 1).

Example 4: Synthesis and Characterization of Compound 4(Oligofluoro-PTX, Covalent Conjugation)

Compound 2-D (1.5 g, 1.36 mmol acid) was dissolved in anhydrous DCM (150mL). The solution was chilled, DIC (0.342 g, 2.71 mmol) was added andthe solution was stirred for 2 hours at room temperature under N₂. DMAP(0.496 g, 4.07 mmol) and PTX (2.31 g, 2.71 mmol) in anhydrous DCM (75mL) were added to the activated Compound 2-D, and the solution was keptwell stirred for three days at room temperature under N₂. The product(Compound 4) was purified with fluorous SPE, and recovered by rotaryevaporation. GPC (dioxane mobile phase): no free PTX was detected, andthe polymer peak had a strong UV absorbance. ¹H NMR (300 MHz, DMSO) δ(ppm) 7.11-8.15 (aromatic H, PTX), 6.24-6.30 (C10), 5.79-5.88 (C3′),5.53-5.63 (C2′ conjugated), 5.32-5.44 (C2), 4.81-4.93 (C5), 4.56-4.62(C7), 4.16-4.35 (—CH₂—O, BAL), 3.84-3.96 (—CH₂—O—CO, PTMO), 3.13-3.40(CH₂—O, PTMO), 2.21-2.27 (OAc, C4), 2.02-2.09 (OAc, C10), 1.68-1.70(C18), 1.04-1.60 (CH₂, PTMO, LDI), 0.90-1.02 (C16, C17).

Example 5: Synthesis and Characterization of Compound 5 (Oligomer-MeOH)

PTMO (15.0 g, 14 mmol) was reacted with LDI (5.9 g, 28 mmol) in DMAc (60mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.MeOH (0.9 g, 28 mmol) was dissolved in DMAc (25 mL), added to thereaction, and stirred at room temperature overnight under N₂. Theproduct (Compound 5) was purified by solvent extraction and cationicSPE. GPC (dioxane mobile phase): 26 minutes. ¹H NMR (300 MHz, CDCl₃) δ(ppm) 4.27-4.39 (—CH—, LDI), 4.02-4.14 (—CH₂—O—CO, PTMO), 3.73-3.78(CH₃, LDI), 3.60-3.70 (—OCH₃, MeOH), 3.30-3.53 (CH₂—O, PTMO), 3.09-3.21(CH₂ —NH, LDI), 1.22-1.91 (PTMO and LDI CH₂).

Example 6: Synthesis and Characterization of Compound 6(TMX-Oligofluoro)

PTMO (15.0 g, 14 mmol) was reacted with TMX (6.79 g, 28 mmol) in DMAc(60 mL) in the presence of DBDL catalyst, at 70° C. for two hours underN₂. Perfluoroalcohol (12.85 g, 30 mmol) was dissolved in DMAc (20 mL),added to the reaction, and stirred at room temperature overnight underN₂. The product (Compound 6) was purified by solvent extraction. GPC(dioxane mobile phase): retention time of 26.5 minutes. ¹H NMR (300 MHz,CDCl₃) δ (ppm) 7.2-7.4 (—CH—, TMX), 4.23-4.37 (—CH₂—O—, BAL), 3.9-4.06(—CH₂—O—CO, PTMO), 3.32-3.52 (CH₂—O, PTMO), 2.29-2.57 (—CH₂—CF₂—, BAL),1.16-1.96 (—CH₂—PTMO and —CH₃ TMX). IR analysis was in accordance withthe chemical structure: 3308 cm⁻¹ ν (N—H) H-bonded, 2936 cm⁻¹ ν (C—H),2852 cm⁻¹ ν (C—H), 1716 cm⁻¹ ν (C═O) urethane amide, 1520 cm⁻¹ ν (C—N),1456 cm⁻¹ ν (C—N), 1362 cm⁻¹ ν (C—O), 1400-1000 cm⁻¹ ν (C—F). DSCanalysis: T_(g)=−55° C. Compound 6 was further purified by dissolving inMeOH and dialyzing for three days using 1000 MWCO regenerated cellulosemembranes (Compound 6-D).

Example 7: Synthesis and Characterization of Compound 7(PCL-Oligofluoro)

PCL diol (10 g, 8 mmol) was reacted with LDI (3.39 g, 16 mmol) in DMAc(17 mL) in the presence of DBDL catalyst, at 70° C. for two hours underN₂. Perfluoroalcohol (7.39 g, 18 mmol) was dissolved in DMAc (20 mL),added to the reaction, and stirred at room temperature overnight underN₂. The product (Compound 7) was purified by solvent extraction andcationic SPE. GPC (dioxane mobile phase): retention time of 26.8minutes, no free PCL diol detected. ¹H NMR (400 MHz, CDCl₃) δ (ppm)4.27-4.48 (—CH₂—O, BAL), 4.17-4.26 (—CH₂—O—CO—N, PCL), 3.96-4.12(—CH₂—O—CO—, PCL), 3.71-3.76 (CH₃, LDI), 3.09-3.22 (CH₂ —NH, LDI),2.39-2.53 (—CH₂—CF₂—, BAL), 2.26-2.38 (CO—CH₂—, PCL), 1.13-1.76 (PCL andLDI CH₂). DSC analysis: T_(g)=−53° C., T_(m)=39° C. Compound 7 wasfurther purified by dissolving in acetone and dialyzing for three daysusing 1000 MWCO regenerated cellulose membranes (Compound 7-D).

Example 8: Synthesis and Characterization of Compound 8(OPCN-Oligofluoro)

Methyl polycarbonate diol (OPCN, 10.0 g, 10 mmol) was reacted with LDI(4.24 g, 20 mmol) in anhydrous DMAc (70 mL) in the presence of DBDLcatalyst, at 70° C. for two hours under N₂. Perfluoroalcohol (9.24 g, 22mmol) was dissolved in anhydrous DMAc (25 mL), added to the reaction,and stirred at room temperature overnight under N₂. The product(Compound 8) was purified by solvent extraction and cationic SPE. GPC(dioxane mobile phase): retention time of 24.7 minutes. ¹H NMR (400 MHz,CDCl₃) δ (ppm) 4.27-4.51 (—CH₂—O, BAL), 3.82-4.07 (—CH₂—O, OPCN),3.65-3.80 (—CH₃, LDI), 3.07-3.27 (CH₂—NH, LDI), 2.32-2.59 (—CH₂—CF₂—,BAL), 1.18-1.94 (CH₂, LDI), 0.84-1.09 (—CH₃, OPCN). DSC analysis:T_(g)=−3° C. Compound 8 was further purified by dissolving in acetoneand dialyzing for three days using 1000 MWCO regenerated cellulosemembranes (Compound 8-D).

Example 9: Synthesis and Characterization of Compound 9(HPCN-Oligofluoro)

Hexamethylene polycarbonate diol (HPCN, 10.0 g, 5 mmol) was reacted withLDI (2.12 g, 10 mmol) in anhydrous DMAc (65 mL) in the presence of DBDLcatalyst, at 70° C. for two hours under N₂. Perfluoroalcohol (4.62 g, 11mmol) was dissolved in anhydrous DMAc (15 mL), added to the reaction,and stirred at room temperature overnight under N₂. The product(Compound 9) was purified by solvent extraction and cationic SPE. GPC(dioxane mobile phase): retention time of 24.2 minutes. ¹H NMR (400 MHz,CDCl₃) δ (ppm) 4.30-4.43 (—CH₂—O, BAL), 3.97-4.22 (—CH₂—O, HPCN),3.69-3.78 (—CH₃, LDI), 3.10-3.23 (CH₂—NH, LDI), 2.37-2.55 (—CH₂—CF₂—,BAL), 1.13-1.89 (CH₂, LDI and HPCN). DSC analysis: T_(g)=−40° C.Compound 9 was further purified by dissolving in acetone and dialyzingfor three days using 1000 MWCO regenerated cellulose membranes (Compound9-D).

Example 10: Synthesis and Characterization of Compound 10 (PEBLDI-Oligofluoro)

PEB diol (14.96 g, 6.0 mmol) was reacted with LDI (2.54 g, 12.0 mmol) inanhydrous toluene (60 mL) in the presence of DBDL catalyst, at 70° C.for two hours under N₂. Perfluoroalcohol (5.541 g, 13.2 mmol) wasdissolved in anhydrous toluene (20 mL) with slight heating, added to thereaction, and stirred at 70° C. overnight under N₂. The product(Compound 10) was purified by solvent extraction and cationic SPE. GPC(THF mobile phase): retention time of 21 minutes. ¹H NMR (300 MHz,CDCl₃) δ (ppm) 4.29-4.45 (CH₂—O, BAL), 4.02-4.11 (—CH—, LDI, —CH—O—CO,PEB), 3.92-4.02 (—CH₂—O—CO, PEB), 3.75 (—CH₃, LDI), 3.10-3.22 (—CH₂—NH—, LDI), 2.38-2.57 (—CH₂—CF₂—, BAL), 0.76-1.92 (—CH₂ PEB and LDI,—CH₃, —CH— PEB). DSC analysis: T_(g)=−16° C.

Example 11: Synthesis and Characterization of Compound 11 (PEBTMX-Oligofluoro)

PEB diol (15.10 g, 6.0 mmol) was reacted with TMX (2.94 g, 12.1 mmol) inanhydrous toluene (60 mL) in the presence of DBDL catalyst, at 70° C.for two hours under N₂. Perfluoroalcohol (5.55 g, 13.2 mmol) wasdissolved in anhydrous toluene (20 mL) with slight heating, added to thereaction, and stirred at 70° C. overnight under N₂. The product(Compound 11) was purified by solvent extraction and cationic SPE. GPC(THF mobile phase): retention time of 21.5 minutes. ¹H NMR (300 MHz,CDCl₃) δ (ppm) 7.20-7.48 (—CH—, TMX), 4.22-4.37 (—CH₂—O, BAL), 3.90-4.03(—CH—O—CO, PEB), 3.85-3.92 (—CH₂—O—CO, PEB), 2.33-2.55 (—CH₂—CF₂—, BAL),0.71-1.72 (—CH₂—, CH₃, —CH—, PEB and —CH₃, TMX). DSC analysis:T_(g)=−13° C.

Example 12: Synthesis and Characterization of Compound 12(HLB-Oligofluoro)

LBH-P hydrogenated hydroxyl terminated polybutadiene (HLB, 10.0 g, 5mmol) was reacted with LDI (2.12 g, 10 mmol) in anhydrous toluene (65mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (4.62 g, 11 mmol) was dissolved in anhydrous toluene(15 mL), brought to 45° C., added to the reaction, and stirred at roomtemperature overnight under N₂. The product (Compound 12) was purifiedby solvent extraction and cationic SPE. GPC (dioxane mobile phase):retention time of 23.9 minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm)4.28-4.46 (—CH₂—O, BAL), 4.00-4.14 (—CH₂—O, HLB), 3.72-3.80 (—CH₃, LDI),3.08-3.22 (CH₂—NH, LDI), 2.37-2.54 (—CH₂—CF₂—, BAL), 0.57-1.75 (CH₂ andCH, LDI and HLB). DSC analysis: T_(g)=−49° C.

Example 13: Synthesis and Characterization of Compound 13(BPH-Oligofluoro)

Neopentyl glycol phthalic anhydride based polyester diol (BPH, 10.0 g,10 mmol) was reacted with LDI (4.24 g, 20 mmol) in anhydrous DMAc (70mL) in the presence of DBDL catalyst, at 70° C. for two hours under N₂.Perfluoroalcohol (9.24 g, 22 mmol) was dissolved in anhydrous DMAc (25mL), added to the reaction, and stirred at room temperature overnightunder N₂. The product (Compound 13) was purified by solvent extractionand cationic SPE. GPC (dioxane mobile phase): retention time of 25.4minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.41-7.79 (aromatic H, BPH),4.25-4.44 (—CH₂—O, BAL), 4.05-4.21 (—CH₂—O, BPH), 3.67-3.79 (—CH₃, LDI),3.06-3.25 (CH₂—NH, LDI), 2.32-2.56 (—CH₂—CF₂—, BAL), 1.26-1.90 (CH₂,LDI), 0.86-1.11 (—CH₃, BPH).

Example 14: Synthesis and Characterization of Compound 14(322-PT-Oligofluoro)

PTMO (5.0 g, 5 mmol) was reacted with LDI (1.59 g, 7.5 mmol) inanhydrous DMAc (35 mL) in the presence of DBDL catalyst, at 70° C. fortwo hours under N₂. Perfluoroalcohol (2.31 g, 5.5 mmol) was dissolved inanhydrous DMAc (10 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product (Compound 14) was purifiedby solvent extraction and cationic SPE. GPC (dioxane mobile phase):retention time of 24 minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.23-4.49(—CH₂—O, BAL), 4.00-4.18 (—CH₂—O, PTMO), 3.69-3.79 (—CH₃, LDI),3.30-3.59, —CH₂—O, PTMO), 3.09-3.25 (CH₂—NH, LDI), 2.37-2.57 (—CH₂—CF₂—,BAL), 1.09-1.94 (CH₂, LDI and PTMO). Elemental analysis: 13.7 wt % F.

Example 15: Synthesis and Characterization of Compound 15(652-PT-Oligofluoro)

PTMO (5.0 g, 5 mmol) was reacted with LDI (1.27 g, 6 mmol) in anhydrousDMAc (35 mL) in the presence of DBDL catalyst, at 70° C. for two hoursunder N₂. Perfluoroalcohol (0.92 g, 2.2 mmol) was dissolved in anhydrousDMAc (5 mL), added to the reaction, and stirred at room temperatureovernight under N₂. The product (Compound 15) was purified by solventextraction and cationic SPE. GPC (dioxane mobile phase): retention timeof 23 minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.27-4.44 (—CH₂-0, BAL),3.98-4.17 (—CH₂—O, PTMO), 3.69-3.79 (—CH₃, LDI), 3.27-3.52, —CH₂—O,PTMO), 3.09-3.22 (CH₂—NH, LDI), 2.34-2.54 (—CH₂—CF₂—, BAL), 1.01-1.90(CH₂, LDI and PTMO). Elemental analysis: 4.3 wt % F.

Example 16: Synthesis and Characterization of Compound 16(12112-PT-Oligofluoro)

PTMO (10.0 g, 10 mmol) was reacted with LDI (2.32 g, 10.9 mmol) inanhydrous DMAc (115 mL) in the presence of DBDL catalyst, at 70° C. fortwo hours under N₂. Perfluoroalcohol (0.84 g, 2 mmol) was dissolved inanhydrous DMAc (5 mL), added to the reaction, and stirred at roomtemperature overnight under N₂. The product (Compound 16) was purifiedby solvent extraction and cationic SPE. GPC (dioxane mobile phase):retention time of 22 minutes. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 4.27-4.44(—CH₂—O, BAL), 3.98-4.17 (—CH₂—O, PTMO), 3.69-3.79 (—CH₃, LDI),3.27-3.52 (—CH₂-0, PTMO), 3.09-3.22 (CH₂—NH, LDI), 2.34-2.54 (—CH₂—CF₂—,BAL), 1.01-1.90 (CH₂, LDI and PTMO). Elemental analysis: 1.3 wt % F.

Example 17: Coating of Compound 1 on a Stent, with Evaluation of CoatingPre and Post Deployment in PBS

Compound 1 (1.0 g) was dissolved in toluene, stirred for 24 hours atroom temperature and kept at room temperature until use. The solutionwas sprayed onto stents using an EFD spray system with settings specificto Compound 1, and the stents were placed in a 50° C. flow oven for20-24 hours for drying. SEM analysis (FIG. 2) indicated a thin coatingwith minimum webbing between struts. In addition, Compound 1 coating wasevaluated after crimping the stent on a balloon and deploying under PBSin 0.125″ID×0.25″OD Sil-Tec medical grade silicone tubing at 37° C.(FIG. 3).

Example 18: Coating of Compound 2 on a Stent

Compound 2 (1.0 g) was dissolved in THF:toluene, stirred for 24 hours atroom temperature and kept at room temperature until use. The solutionwas sprayed onto stents using an EFD spray system with settings specificto Compound 2, and the stents were placed in a 50° C. flow oven for20-24 hours for drying. SEM analysis (FIG. 4) suggested a thin coatingwith minimal webbing between struts.

Example 19: Coating of Compound 3 on a Stent, with Evaluation of CoatingPre and Post Deployment in Air

Compound 3 (0.2 g) was dissolved in THF:toluene, stirred for 24 hours atroom temperature, and used immediately. The solution was sprayed ontostents using an EFD spray system with settings specific to Compound 3,and the stents were placed in a 50° C. flow oven for 20-24 hours fordrying. Confocal/fluorescence microscopy images were taken and indicatedthe presence of coating on the stents (FIG. 5). In addition, Compound 3coating had sufficient integrity during product processing, includingcrimping on a balloon (FIG. 6) and deployment in air (FIG. 7).

Example 20: Coating of Compound 4 on a Stent and Release of PTX intoTween PBS

Compound 4 (0.2 g) was dissolved in toluene and stirred for 24 hours atroom temperature. The solution was sprayed onto stents using an EFDspray system with settings specific to Compound 4, and the stents weredried in a 50° C. flow oven for 20-24 hours. SEM analysis (FIG. 8)indicated a thin coating with minimum webbing between struts. PTXrelease was investigated at 37° C. with Tween PBS. Tween PBS (1 mL) wasadded to each stent and changed daily. PTX release was measured usingRP-HPLC with benzonitrile as the internal standard: (ng/ml): (day 1)=32,(day 2)=25, (day 3)=22, (day 4)=6, (day 5)=3, (day 6)=2.

Example 21: Coating of Compound 5 on a Stent

Compound 5 (0.2 g) was dissolved in toluene, stirred for 24 hours atroom temperature, and stored at room temperature until use. The solutionwas sprayed onto stents using an EFD spray system with settings specificto Compound 5, and the stents were placed in a 50° C. flow oven for20-24 hours for drying. SEM images (FIG. 9) suggested a thin coatingwith minimum webbing between struts.

Example 22: Coating of Compound 6 on a Stent

Compound 6 (0.2 g) was dissolved in toluene, stirred for 24 hours atroom temperature, and stored at room temperature until use. The solutionwas sprayed onto stents using an EFD spray system with settings specificto Compound 6, and the stents were placed in a 50° C. flow oven for20-24 hours for drying. SEM images (FIG. 10) indicated a thin coatingwith minimum webbing between struts.

Example 23: Coating of Compound 7 on a Stent

Compound 7 (0.2 g) was dissolved in toluene, and stirred for 24 hours atroom temperature until used for coating. The solution was sprayed ontostents using an EFD spray system with settings specific to Compound 7.The stents were dried in a 50° C. flow oven for 20-24 hours. SEM imagecollection was used to validate the coating quality (FIG. 11).

Example 24: Coating of Compound 8 on a Stent

Compound 8 (0.4 g) was dissolved in THF, stirred for 24 hours at roomtemperature and used for coating. The solution was sprayed onto stentsusing an EFD spray system with settings specific to Compound 8. Thestents were dried at room temperature in a fume hood for 24 hours. SEMimages (FIG. 12) indicated a thin coating with minimum webbing betweenstruts.

Example 25: Coating of Compound 9 on a Stent

Compound 9 (0.4 g) was dissolved in THF, stirred for 24 hours at roomtemperature and used for coating. The solution was sprayed onto stentsusing an EFD spray system with settings specific to Compound 9. Thestents were dried at room temperature in a fume hood for 24 hours. SEMimages (FIG. 13) indicated a thin coating with minimum webbing betweenstruts.

Example 26: Coating of Compound 10 on a Stent

Compound 10 (0.2 g) was dissolved in toluene, stirred for 24 hours atroom temperature and used for coating. The solution was sprayed ontostents using an EFD spray system with settings specific to Compound 10.The stents were dried in a 50° C. flow oven for 20-24 hours. SEM images(FIG. 14) indicated a thin coating with minimum webbing between struts.

Example 27: Coating of Compound 11 on a Stent

Compound 11 (0.2 g) was dissolved in toluene, stirred for 24 hours atroom temperature and used for coating. The solution was sprayed ontostents using an EFD spray system with settings specific to Compound 11.The stents were dried in a 50° C. flow oven for 20-24 hours. SEM images(FIG. 15) indicated a thin coating with minimum webbing between struts.

Example 28: Coating of Compound 12 on a Stent

Compound 12 (0.4 g) was dissolved in chloroform, stirred for 24 hours atroom temperature and used for coating. The solution was sprayed ontostents using an EFD spray system with settings specific to Compound 12.The stents were dried at room temperature in a fume hood for 3 days. SEMimages (FIG. 16) indicated a thin coating with minimum webbing betweenstruts.

Example 29: Coating of Compound 14 on a Stent

Compound 14 (0.4 g) was dissolved in THF, stirred for 24 hours at roomtemperature and used for coating. The solution was sprayed onto stentsusing an EFD spray system with settings specific to Compound 14. Thestents were dried at room temperature in a fume hood for 3 days. SEMimages (FIG. 17) indicated a thin coating with minimum webbing betweenstruts.

Example 30: Coating of Compound 15 on a Stent

Compound 15 (0.4 g) was dissolved in THF, stirred for 24 hours at roomtemperature and used for coating. The solution was sprayed onto stentsusing an EFD spray system with settings specific to Compound 15. Thestents were dried at room temperature in a fume hood for 3 days. SEMimages (FIG. 18) indicated a thin coating with minimum webbing betweenstruts.

Example 31: Coating of Compound 1+Compound 7 on a Stent

Compound 1 (0.2 g) was dissolved in THF and added to Compound 7 (0.2 g)that was dissolved in THF. The resulting solution was stirred for 24hours at room temperature and used for coating. The solution was sprayedonto stents using an EFD spray system with settings specific to Compound1+7. The stents were dried at room temperature in a fume hood for 3days. SEM images (FIG. 19) indicated a thin coating with minimum webbingbetween struts.

Example 32: Preparation of Compound 2+8.8 wt % PTX, and Coating on aStent

Compound 2 (0.332 g) and PTX (0.032 g) were dissolved in THF:toluene,stirred for 24 hours at room temperature, and used immediately. Thesolution was sprayed onto stents using an EFD spray system with settingsspecific to Compound 2+PTX, and the stents were placed in a 50° C. flowoven for 20-24 hours for drying. SEM analysis (FIG. 20) indicated a thincoating with minimum webbing between struts.

Example 33: Preparation of Compound 6+8.8 wt % PTX, and Coating on aStent

Compound 6 (0.332 g) and PTX (0.032 g) were dissolved in THF:toluene,was stirred for 24 hours at room temperature, and used immediately. Thesolution was sprayed onto stents using an EFD spray system with settingsspecific to Compound 6+8.8 wt % PTX, and the stents were placed in a 50°C. flow oven for 20-24 hours for drying. SEM analysis (FIG. 21)indicated a thin coating with minimum webbing between struts.

Example 34: Combination of Compounds 1, 2, 5, 6 and 7 with SalicylicAcid (SA) and the Release Profile of SA

Compounds 1, 2, 5, 6 and 7 (0.075 g) were mixed with SA (0.025 g) inMeOH under nitrogen protection, stirred, and were separated from solventby rotary evaporation and vacuum drying. Controls were also prepared:Compounds 1, 2, 5, 6, and 7 (0.075 g) were dissolved in MeOH and wereseparated from solvent by rotary evaporation and vacuum drying. To eachvial (Compounds with SA and controls) PBS (10 mL) was added, and SArelease was measured from diluted samples using a UV/Visspectrophotometer at 294 nm at 1, 2, 3, 4, 6 and 24 hours. ABeer-Lambert calibration plot was prepared using solutions of SA (0-0.05mg/mL SA). Compound 1+SA: (1 hour)=1.137, (2 hour)=0.248, (3hour)=0.120, (4 hour)=0.247, (6 hour)=0.136, (24 hour)=0.651. Compound2+SA: (1 hour)=1.249, (2 hour)=0.316, (3 hour)=0.084, (4 hour)=0.207, (6hour)=0.305, (24 hour)=0.373. Compound 5+SA: (1 hour)=0.518, (2hour)=0.230, (3 hour)=0.166, (4 hour)=0.268, (6 hour)=0.583, (24hour)=0.873. Compound 6+SA: (1 hour)=0.882, (2 hour)=0.364, (3hour)=0.218, (4 hour)=0.282, (6 hour)=0.424, (24 hour)=0.687. Compound7+SA: (1 hour)=0.689. The chemical composition and functional groupswith in the formulation highlights the tunability of the coating matrixfor a desired release profile. The amount of SA in media shows theability of the platform to not only interact but also release thepharmaceutical component.

Example 35: Release of PTX from Compounds 1, 2, and 6 into Tween PBS

Compounds 1, 2, and 6 were combined with PTX at 5, 8.8 and 20 wt % inDCM, and aliquots of each solution (0.1 mL) were transferred to 4 mLglass vials in duplicate. The solvent was flashed off, and the vialswere dried under vacuum at ambient temperatures. Tween PBS (1 mL) wasadded to each vial, and the vials were incubated at 37° C. After 1 hour,the buffer was withdrawn and PTX content was analyzed by HPLC (FIG. 22).

Example 36: Release of PTX from Compounds 1 and 6 into Tween PBS

Compounds 1 and 6 were combined with PTX at 5 and 8.8 wt % in DCM, andaliquots of each solution (0.1 mL) were transferred to 4 mL glass vialsin duplicate. Tween PBS (1 mL) was added to each vial, and the vialswere incubated at 20 and 37° C. At selected time-points (1, 2, 3, 4, and5 days) the buffer was withdrawn for PTX analysis by HPLC (FIGS. 23 and24) and replenished with Tween PBS (1 mL).

Example 37: Release of PTX from Compounds 1 and SIBS into Tween PBS

Compound 1 and SIBS were weighed into 4 mL glass vials as described inTable 1, and were dissolved in THF:toluene. PTX (0.04 g) was dissolvedin THF:toluene, and PTX solution was added the Compound 1 and SIBSsolutions (0.001 g PTX per vial) and mixed overnight. The solvent wasrapidly removed from each vial under vacuum and dried overnight. TweenPBS (1 mL) was added to each vial, and the release of PTX was measuredby HPLC after 24 hours (Table 1).

TABLE 1 Preparation of PTX-containing mixtures of Compound 1 and SIBS,and release of PTX into Tween PBS. Release of PTX Mass Wt % (ng/mL)after 24 Compound PTX (g) PTX hours Compound 1 0.001 0.5 5029 Compound 11   10409 Compound 1 8.8 68694 SIBS 8.8 3356The data shows the enhanced differences in efficiency betweenconventional base polymer drug release and self eliminating drugrelease.

Example 38: Preparation of Compound 1+8.8 wt % PTX, Coating on a Stentand Release Profile of PTX

Compound 1 (0.33 g) was dissolved in THF:toluene, mixed with a PTXsolution (0.032 g/mL), stirred for 24 hours at room temperature, andused immediately. The solution was sprayed onto stents using an EFDspray system with settings specific to Compound 1+8.8 wt % PTX, and thestents were dried in a 50° C. flow oven for 20-24 hours. SEM analysis(FIG. 25) indicated a thin coating with minimum webbing between struts.Tween PBS or MilliQ water (1 mL) was added to each stent, and incubatedat 37° C., with Tween PBS and water changed daily. PTX release wasmeasured using RP-HPLC with benzonitrile as the internal standard: TweenPBS (ng/mL): (day 1)=9731, (day 2)=4330, (day 3)=2523, and water(ng/mL): (day 1)=2810, (day 2)=1489, (day 3)=1146.

Example 39: Preparation of Compound 1, 6, 7, 1+7, 8, 9, and 12+1 wt %PTX, Coating on a Stent and Release Profile of PTX into Tween PBS andWater

Compounds 1, 6, 7, 1+7, 8, 9, and 12 (0.4 g) were dissolved in THF,mixed with a PTX solution (0.032 g/mL), stirred for 24 hours at roomtemperature, and used immediately. The solutions were sprayed ontostents using an EFD spray system with settings specific to eachCompound+1 wt % PTX. The stents were dried at room temperature in a fumehood for 4 days. SEM analyses (FIG. 26 a-g) indicated thin coatings withminimum webbing between struts for all coatings. PTX release wasinvestigated at 37° C. in Tween PBS and in MilliQ water (Tween PBS onlyfor Compound 1+7). Tween PBS or water (1 mL) was added to each stent andchanged daily. PTX release was measured using RP-HPLC with benzonitrileas the internal standard: Compound 1 (Tween PBS (ng/mL): (day 1)=889,(day 2)=743, (day 3)=354, and water (ng/mL): (day 1)=669, (day 2)=488,(day 3)=367. Compound 6 (Tween PBS (ng/mL): (day 1)=1106, (day 2)=816,(day 3)=536, (day 4)=279, (day 5)=168, and water (ng/mL): (day 1)=641,(day 2)=596, (day 3)=441, (day 4)=345, (day 5)=320. Compound 7 (TweenPBS (ng/mL): (day 1)=1161, (day 2)=888, (day 3)=932, (day 4)=600, (day5)=397, (day 6)=453, (day 7)=399, (day 8)=331, (day 9)=272, and water(ng/mL): (day 1)=588, (day 2)=500, (day 3)=434, (day 4)=397, (day5)=332, (day 6)=299, (day 7)=292, (day 8)=238, (day 9)=201. Compound 1+7(Tween PBS (ng/mL): (day 1)=808, (day 2)=735, (day 3)=701, (day 4)=546.Compound 8 (Tween PBS (ng/mL): (day 1)=1338, (day 2)=1040, (day 3)=878,(day 4)=571, (day 5)=409, and water (ng/mL): (day 1)=928, (day 2)=593,(day 3)=681, (day 4)=681, (day 5)=646. Compound 9 (Tween PBS (ng/mL):(day 1)=804, (day 2)=628, (day 3)=421, and water (ng/mL): (day 1)=498,(day 2)=334, (day 3)=250. Compound 12 (Tween PBS (ng/mL): (day 1)=1086,and water (ng/mL): (day 1)=1717. The chemical composition and functionalgroups with in the formulation highlights the tunability of the coatingmatrix for a desired release profile. The amount of PTX in media showsthe ability of the platform to not only interact but also release thepharmaceutical component.

Example 40: Release of PTX from Compound 1+8.8 wt % PTX on StainlessSteel Coupon after Contact with Cardiac Muscle

Compound 1 (0.40 g) and PTX (0.0386 g) were dissolved in toluene:THF andstirred overnight. Stainless steel coupons (1.5 g) with dimensions ofapproximately 3.5 cm×1 cm were immersed in acetone, sonicated for 45minutes, and were dried in a 50° C. flow oven overnight. One side ofeach coupon was coated with the solution, and the average mass ofCompound 1+PTX on individual coupons was measured (0.005-0.008 g). Thecoated sides of the stainless steel coupons were placed in contact withcardiac muscle (7.0-13.0 g), and were secured with umbilical tape (FIG.27). At selected time-points (1 and 24 hours), triplicate test articlesand duplicate control articles were removed, rinsed with water, anddried at 50° C. overnight in a flow oven (FIG. 28). The coating was thenstripped off with THF (15 mL) for 3 days, and an aliquot (1 mL) of thestripping solution was submitted for HPLC analysis (acetonitrile: watermobile phase) to determine the average PTX remaining on the coupons(FIG. 29).

Example 41: Release of PTX from Compound 1+1 wt % PTX on Stainless SteelCoupon after Contact with Cardiac Muscle

Compound 1 (0.405 g) and PTX (0.004 g) were dissolved in toluene:THF andstirred overnight. Stainless steel coupons (1.5 g) with dimensions ofapproximately 3.5 cm×1 cm were immersed in acetone, sonicated for 45minutes, and dried in 50° C. flow oven overnight. One side of eachcoupon was coated with the solution, and the average mass of Compound1+PTX on individual coupons was measured (0.005-0.008 g). The coatedsides of the stainless steel coupons were placed in contact with cardiacmuscle (7.0-13.0 g), and were secured with umbilical tape. At selectedtime-points (1 and 24 hours), triplicate test articles and duplicatecontrol articles were removed, rinsed with water, and dried in 50° C.flow oven overnight. The coating was then stripped off with THF (15 mL)for 3 days and an aliquot (1 mL) of stripping solution was submitted forHPLC analysis (acetonitrile: water mobile phase) to determine theaverage PTX remaining on the coupons (FIG. 30).

Example 42: Release of PTX from Compound 1+8.8 wt % PTX on StainlessSteel Coupon in Porcine Blood

Stainless steel coupons prepared as in Example 40 were incubated inporcine blood (4 mL). After 1 hour, triplicate test articles andduplicate control articles were rinsed with water, dried at 50° C.overnight, and weighed. The coatings were then stripped off with THF (15mL) for 3 days and an aliquot

(1 mL) of stripping solution was submitted for HPLC analysis(acetonitrile: water mobile phase) to determine the average PTXremaining on the coupons. Control (ng/mL): (by weight)=32888,(HPLC)=38405. 1 hour sample (ng/mL): (by weight)=34667, (HPLC)=40962.

Example 43: Residency Time of Compounds 1, 2, 3, 6, 7, 1+7, 8, 9, 10,11, 12, 14, 15 and 16 Under Sink Condition in PBS

All vials were pre-dried in the oven overnight and tared. Compounds 1,2, 3, 6, 7, 1+7, 8, 9, 10, 11, 12, 14, 15 and 16 (0.2 g) were weighedinto the vials, PBS was added (4 mL), and each vial was then incubatedat 37° C. At selected time-points (1, 3, 7, 14 and 21 days) vials wereisolated and rinsed with copious amounts of water to remove residualsalt, dried in a 50° C. flow oven overnight, and weighed. The residencytime was calculated by measuring the percentage of mass loss at eachtime point (FIG. 31).

Example 44: Residency of Compounds 1, 2, 1+7, 10 and 12 on StainlessSteel Coupons, Under Sink Condition in PBS

Compound 1 (0.20 g), Compound 10 (0.22 g), and Compound 12 (0.20 g) weredissolved in toluene. Compound 1+7 (0.20 and 0.30 g) was dissolved inTHF, and Compound 2 (0.20 g) was dissolved in THF: toluene. Stainlesssteel coupons (1.5 g) with dimensions of approximately 3.5 cm×1 cm wereimmersed in acetone, sonicated for 45 minutes, and dried in a 50° C.flow oven overnight. Both sides of the coupons were coated with eachCompound solution and the average weight of Compound was measured(0.020-0.040 g). Every coupon was placed in a vial and incubated withPBS (15 mL) at 37° C. At selected time-points (1 and 14 days), thecoupons were isolated and rinsed with copious amounts of water and driedin a 50° C. flow oven. The residency time was calculated by measuringthe percentage of mass loss at each time point (FIG. 32).

Example 45: Residency Time of Compound 1, 2, 6, 1+7, 10 and 12 UnderSink Condition in Porcine Blood

All vials were pre-dried in the oven overnight and tared. Compounds 1,2, 6, 1+7, 10 and 12 (0.2 g) were weighed into the vials, porcine blood(4 mL) was added to each vial, and incubated at 4° C. At selectedtime-points (1, 3, 7 and 14 days), vials were isolated and rinsed withcopious amounts of water and dried in a 50° C. flow oven overnight. Theresidency time was calculated by measuring the percentage of mass lossafter incubation at each time point (FIG. 33).

Example 46: Residency Time of Compounds 1, 2, 10, and 12 on StainlessSteel Coupons Under Sink Condition in Porcine Blood

Compound 1 (0.20 g), Compound 10 (0.22 g), and Compound 12 (0.20 g) weredissolved in toluene. Compound 2 (0.20 g) was dissolved in THF: toluene.Stainless steel coupons (1.5 g) with dimensions of approximately 3.5cm×1 cm were immersed in acetone, sonicated for 45 minutes, and dried ina 50° C. flow oven overnight. Both sides of the coupons were coated witheach Compound solution, the average weight of Compound was measured(0.020-0.040 g), and incubated with porcine blood (15 mL) at 4° C. Atselected time-points (1 and 14 days) coupons were isolated and rinsedwith copious amounts of water and dried in a 50° C. flow oven. Theresidency time was measured by the percentage of mass loss at the end ofeach time point (FIG. 34).

Example 47: Residency Time of Compounds 1, 2, 6, 7, 1+7, 10, and 12Under Sink Condition in Artificial Urine

All vials were pre-dried in the oven overnight and tared. Compounds 1,2, 6, 7, 1+7, 10, and 12 (0.2 g) were weighed in the vials and incubatedin artificial urine (4 mL) at 37° C. At selected time-points (1, 3, 7,14, and 21 days), vials were isolated, rinsed with copious amounts ofwater, dried in a 50° C. flow oven overnight, and weighed. The residencytime was calculated by measuring the percentage of mass loss afterincubation (FIG. 35).

Example 48: Residency Time of Compound 1, 2, 4, 6 Under Flow Conditionin PBS

Compounds 1, 2, 4 and 6 (1.05 g) were dissolved in toluene. Stainlesssteel coupons (1.5 g) with dimensions of approximately 3.5 cm×1 cm wereimmersed in acetone, sonicated for 45 minutes, and dried in a 50° C.flow oven overnight. Both sides of the coupons were coated with theCompound solutions and the average weight of Compound was measured(0.008-0.012 g). Silicone tubing and PVC tubing were cut 5 cm and 3 cmin length, respectively. Each of the coated coupons were inserted into asilicone tubing segment and labeled. All silicone tubing segments werethen connected together by PVC tubing. Clean silicone tubing (100 cm)was wrapped around the head of a peristaltic pump. The outlet wasconnected to the silicone tubing segments containing coated coupons. PBSwas pumped aggressively through the loop system from a PBS reservoir(1000 mL). At selected time-points (2 and 6 hours for Compounds 1, 2,and 6, and 0.5, 1, and 2 hours for Compound 4) triplicate coupons wereisolated and rinsed with water several times, dried, and weighed. Theresidency times were calculated by measuring the percentage of mass lossafter each time-point (FIG. 36).

Example 49: Residency Time of Compound 1, 2 and 6 Under Flow Conditionin Porcine Blood

Compounds 1, 2, and 6 (0.50 g) were dissolved in toluene. Stainlesssteel coupons (1.5 g) with dimensions of approximately 3.5 cm×1 cm wereimmersed in acetone, sonicated for 45 minutes, and dried in a 50° C.flow oven overnight. Both sides of the coupons were coated with Compoundsolutions and the average mass of Compound was measured (0.008 to 0.012g). Silicone tubing and PVC tubing were cut 5 cm and 3 cm in length,respectively. Each of the coated coupons were inserted into a siliconetubing segment and labeled. All silicone tubing segments were thenconnected together by PVC tubing. Clean silicone tubing (100 cm) waswrapped around the head of a peristaltic pump. The outlet was connectedto the silicone tubing segments containing coated coupons. Porcine bloodwas pumped aggressively through the loop system from a porcine bloodreservoir (1000 mL). At selected time-points (2 and 6 hours) triplicatecoated coupons and duplicate control coupons were isolated, rinsed withwater several times, dried, and weighed. The residency time wascalculated by measuring the percentage of mass loss after incubation ateach time point (FIG. 37).

Example 50: Residency Time of Compound 1, 2 and 6 Under Flow Conditionin Artificial Urine

Compounds 1, 2 and 6 (0.50 g) were dissolved in toluene. Stainless steelcoupons (1.5 g) with dimensions of approximately 3.5 cm×1 cm wereimmersed in acetone, sonicated for 45 minutes, and dried in 50° C. flowoven overnight. Both sides of the coupons were coated with Compoundsolutions and the average mass of Compound was measured (0.008 to 0.012g). Silicone tubing and PVC tubing were cut 5 cm and 3 cm in length,respectively. Each of the coated coupons were inserted into a siliconetubing segment and labeled. All silicone tubing segments were thenconnected together by PVC tubing. Clean silicone tubing (100 cm) waswrapped around the head of a peristaltic pump. The outlet was connectedto the silicone tubing segments containing coated coupons. Artificialurine was pumped aggressively through the loop system from an artificialurine reservoir (1000 mL). At selected time-points (2 and 6 hours)triplicate coated coupons and duplicate control (uncoated) coupons wereisolated, rinsed with water several times, dried, and weighed. Theresidency time was calculated by measuring the percentage of mass lossafter incubation at each time point (FIG. 38).

Example 51: Residency Time of Compounds 1, 2 and 6 in Porcine Heart

Compounds 1, 2, and 6 (0.5 g) were dissolved in toluene. Stainless steelcoupons (1.5 g) with dimensions of approximately 3.5 cm×1 cm wereimmersed in acetone, sonicated for 45 minutes, and dried in a 50° C.oven overnight. Both sides of the coupons were coated with Compound 1, 2and 6 solutions and the average mass of Compound was measured (0.008 to0.012 g). Porcine hearts were thawed and washed with water. A pocketincision 5.5 cm wide was made in the left ventricle of the porcinehearts using a scalpel. The incisions penetrated into the ventriclecavity (FIG. 39). Each coated coupon or control article was insertedinto the incision, and the hearts were sutured with Ethi-pack 3161 tohold the incision closed. Porcine hearts were placed inside individualplastic containers and placed in a 37° C. room. At selected time-points(4 and 24 hours) triplicate coupons and duplicate control coupons(uncoated) were isolated and removed from the porcine hearts, washedwith copious amounts of water, dried in a 50° C. oven, and weighed. Theresidency time was calculated by measuring the percentage of mass lossat each time point: Compound 1: (4 hours)=26.7%, (24 hours)=63.1%.Compound 2: (4 hours)=58.2%, (24 hours)=63.0%. Compound 6: (4hours)=26.6%, (24 hours)=51.7%.

Example 52: Long Term Residency Study of Compounds 1, 2, 3, 6, 7, 1+7,8, 9, 10, 11, 12, 14, 15, 16 in PBS Sink Condition

Compounds 1, 2, 3, 6, 7, 1+7, 8, 9, 10, 11, 12, 14, 15, and 16(0.16-0.20 g) were weighed into pre-dried vials and incubated in PBS (4mL) at 37° C. At selected time-points (1, 3, 7, 14, 21, 30, 45, 60, 75,90, 105, 120, 135, 150 days) the PBS was withdrawn, and the Compoundswere rinsed with water and dried in a 50° C. flow oven overnight.Compounds were weighed the following day and re-incubated with PBS at37° C. The cycle of PBS removal-water rinsing-drying-re-incubation wasrepeated until day 150. The residency time was measured by thepercentage of mass loss of each Compound at each time point (FIG. 40).

Example 53: Determination of the Partition Coefficient of Compounds 1,2, 3, 6, 7, 8, 9, 10, 11, 12, SIBS and PTX

The partitioning of Compounds synthesized in Examples 1-13 was measuredin a 1-octanol/PBS system. The partitioning correlates with thelipophilicity of the Compounds, and is used to predict the adsorptionand distribution of Compounds under investigation. 1-octanol and PBSwere thoroughly mixed to provide PBS-saturated 1-octanol in the topphase and 1-octanol-saturated PBS in the bottom phase. Solutions ofCompounds 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 16, PTX, and SIBS (0.05 mL)were added to each vial of 1-octanol/PBS. The vials were rocked for 4hours, ensuring good contact between the phases. An aliquot of theorganic phase from each sample was then analyzed by GPC (THF mobilephase, RI), which had been calibrated using known concentrations of eachcompound. The area under the RI peak was used to estimate theconcentration of each compound in the organic phase. The mass of eachCompound was then used to calculate the weight percentage in organicphase by the following formula: (mass of Compound in 1-octanolphase/total mass)×100%. The partition coefficient was calculatedaccording to the following formula: log([Compound in1-octanol]/[Compound in PBS]). Results (wt % in 1-octanol, partitioncoefficient): Compound 1 (86%, 0.80), Compound 2 (78%, 0.54), Compound 3(96%, 1.42), Compound 6 (86%, 0.80), Compound 7 (85%, 1.50), Compound 8(94%, 1.20), Compound 9 (91%, 1.00), Compound 10 (93%, 1.14), Compound11 (99%, 2.37), Compound 12 (98%, 1.64), SIBS (93%, 1.54), PTX (94%,1.00).

Example 54: Determination of the Solubility of Compounds 1, 2, 6, 7, 8,9, 12, 14, 15 and 16 in Tween PBS and Water

Compounds 1, 2, 6, 7, 8, 9, 12, 14, 15, and 16 (0.05 g) were incubatedin Tween PBS or water for 24 hours at room temperature. Tween PBSsolutions and water were withdrawn and filtered through 0.45 μm filterdiscs and dried in a flow oven at 50° C. for 2 days. Dried samples wereanalyzed by ¹H NMR, and the soft segment assignments were used toquantitatively measure Compound solubility in each environment. ¹H NMR(Reference: 20353.52, Compound 1 (Tween PBS): 251.68, Compound 1(water): 41.82, Compound 2 (Tween PBS): 818.37, Compound 6 (Tween PBS):52.32, Compound 6 (water): 24.57, Compound 14 (Tween PBS): 76.84,Compound 15 (Tween PBS): 83.27, Compound 16 (Tween PBS): 90.04). ¹H NMR(Reference: 15434.13, Compound 7 (Tween PBS): 88.32, Compound 7 (water):17.63). ¹H NMR (Reference: 53909, Compound 8 (water): 23.43). ¹H NMR(Ref: 35697.31, Compound 9 (Tween PBS): 106.42). ¹H NMR (Reference:19736.11, Compound 12 (Tween PBS): 1001.88, Compound 12 (water):1804.78).

Example 55: Stability of Compounds 1, 5, 7, and DL-PLGA in DifferentMedia

Compounds 1, 5 and 7 (0.06 g×4 each) were weighed into glass vials andincubated at 37° C. for 3 days in PBS, 10 mM NaOCl, 1N NaOH, and 1N HCl(10 mL). DL-PLGA (0.3 g) was dissolved in DCM (1.5 mL), and 0.3 mL ofthis solution was transferred into glass vials. The solvent was drivenoff in a 60° C. flow oven followed by overnight vacuum drying. The filmswere then incubated at 37° C. for 3 days in PBS, 10 mM NaOCl, 1N NaOH,and 1N HCl (10 mL). The weight change (FIG. 41) and GPC profile of eachsample was recorded before and after incubation.

Example 56: Sterilization of Compounds 1,1-D, 2, 3, 6, 6-D, 7-D, 8-D,9-D, 10, 11, 12, 14, 15, and 16 by Ethylene Oxide

Compounds 1, 2, and 6 (0.115 g) were weighed into a glass vial andmelted at 50° C. for 30 minutes to form an even layer on the vialbottom. After chilling, the vials were capped with a lint-free tissue,placed in a sterilization pouch, and sterilized by EtO. No changes tothe analytical profile were observed. Compounds 1-D, 3, 6-D, 7-D, 8-D,9-D, 10, 11, 12, 14, 15, and 16 (0.15 g) were weighed into polypropyleneconical tubes capped with lint-free tissue, placed in sterilizationpouches, and were sterilized by EtO. The sterilized compounds wereanalyzed, and these results were compared to the pre-sterilizationprofile. No changes were observed for pre and post sterilizationsamples. Residual EtO content: ethylene oxide=2 ppm, ethylenechlorohydrin=13 ppm, ethylene glycol<100 ppm. LAL testing: <0.020 EU/mLin the sample extract.

Example 57: Porcine Blood Interaction with Films of Compounds 1, 6, 7,1+7, 8, 9, 10, 11, 12, 14 and 15

SPINCOATED FILMS: Compound 1 (0.5 g) was dissolved in toluene. A clean4×4 cm stainless steel coupon was placed on the chuck of a SpecialtyCoating Systems spin-coater, spun at 2000 rpm, and Compound 1 solution(0.15 mL) was applied. The resulting smooth coatings were analyzed bySEM to confirm continuous coverage, and scratched to confirm thepresence of coating. XPS analysis (90°) was performed to obtain surfaceelemental analysis, and to examine for evidence of incomplete coating.Stainless steel: C: 27.84%, Ca: 0.40%, F: 1.18%, Mo: 0.48%, N: 1.18%,Na: 0.46%, O: 52.39% Si: 5.89%, Cr: 3.03%, Fe: 7.15%. Compound 1coating: C: 51.55%, Ca: 0.36%, F: 31.32%, Mo: 0.02%, N: 3.85%, Na: 0%,Si: 0.06%, Cr: 0%, Fe: 0.01%.

SPRAYED FILMS: Compounds 1 (0.4 g), Compound 6 (0.4 g), Compound 10 (0.2g), Compound 11 (0.2 g), Compound 12 (0.4 g), Compound 14 (0.2 g), andCompound 15 (0.2 g) were dissolved in toluene. Similarly, Compounds 7,1+7, 8, and 9 (all 0.4 g) were dissolved in THF. The solutions werestirred for 24 hours at room temperature and were sprayed onto 316stainless steel coupons ranging in total surface area from 6.25 cm² to16 cm², using an EFD spray system with settings specific to eachCompound. The coupons were dried in a 50° C. flow oven for 20-24 hours.SEM images (FIG. 42) indicated a smooth, even coating for most compoundsexcept for Compounds 10 and 11. These compounds had a slightly rough buteven coating. Contact angle analyses of the coated coupons wereperformed with water and porcine plasma: stainless steel (water: 59°,plasma: 58°), Compound 1 (water: 107°, plasma:104°), Compound 7 (water:88°, plasma:89°), Compound 1+7 (water: 90°, plasma:85°), Compound 12(water: 114°, plasma:119°), Compound 15 (water: 116°, plasma:116°). Noappreciable changes to the coating surfaces were noted when incubated inporcine blood for 15 minutes at room temperature (FIG. 43).

Example 58: Evaluation of Inflammatory Cell Response to Compounds 1, 2,6, 7, 1+7, 8, 9, 15 and 16

Compounds 1, 2, 6, 7, 1+7, 8, 9, 15, and 16 were dissolved in THF ortoluene, and were cast into 96 well polypropylene plates. The solventwas evaporated off at room temperature for 24 hours, the plates werethen placed in a 60° C. flow oven for 24 hours, and finally dried undervacuum overnight. For comparison purposes, films of SIBS and 316stainless steel inserts were added to the plates. The plates weresterilized under a UV lamp for 1 hour, after which each sample well washydrated with PBS. U937 monocyte-like cells (2.5×10⁵ cells) were seededinto each well in the presence of PMA, and the plates were incubated at37° C. in a humid incubator for three days. Non-adherent cells wereremoved, and adherent U937 macrophages were enumerated using a CyQuantassay (FIG. 44). The same experimental procedure was applied to allCompounds described in Examples 1 to 16.

Example 59: Migration of HCAEC Through Membranes Coated with Compound 1,and Compound 1+1 and 10 wt % PTX

Compound 1 (0.1 g) was dissolved in MeOH (0.5, 1, 2 and 4 mL), and thesesolutions (0.05 mL) were pipetted onto and wicked through a BD 8 μm PETmembrane insert. Compound 1 was also blended with PTX to form 1 and 10wt % solutions, and these were coated onto membranes. As a control, asolution of SIBS polymer of suitable concentration was coated ontomembranes. The resulting coated membranes were examined by SEM andporosity was confirmed by the passage of water through the membranes.Further, Compound 6 (fluorescently labeled form of Compound 1) wascoated using the same method, and fluorescence (Ex 320, Em 540 nm) wasmeasured to confirm the presence of coating: (uncoated membrane)=3.5,(Compound 1)=0.6, (Compound 6)=28.2. HCAEC were cultured to thirdpassage using media and supplements supplied by Lonzo, and were starvedin serum-free media overnight. Cells were lifted and re-suspended in0.5% FBS media, and HCAEC were seeded (80000 per membrane insert). Thelower wells were filled with 20% FBS media. The negative controlconsisted of an uncoated membrane with 0.5% FBS media in the lower well.The positive control consisted of an uncoated membrane with 20% FBSmedia in the lower well. After four hours of incubation, the wells werelifted out, the inner membranes were scrubbed free of cells, and thelower membrane surface was fixed and stained with DiffQuik. Images ofthe membranes were collected by microscopy, and cell morphologycharacteristics and population were recorded (FIG. 45). The sameexperimental procedure was applied to all Compounds described inExamples 1 to 16.

The migration assay as described for the HCAEC was repeated with celllines from other species on all Compounds described in Examples 1-16.

Example 60: Evaluation of Platelet and Fibrinogen Interaction with Filmsof Compounds 1, 7, 1+7, and 12

Compounds 1, 7, 1+7, and 12 were dissolved in toluene or THF. AllCompound solutions were stirred for 24 hours at room temperature andused for coating. The solutions were sprayed onto 4 cm×4 cm 316Lstainless steel coupons using an EFD spray system with settings specificto each Compound. The coupons were dried in a 50° C. flow oven for 20-24hours. Human whole blood was obtained from healthy drug-free volunteersand collected in centrifuge tubes with either acid citrate dextroseanti-coagulant (6 parts ACD to 1 part blood) or low molecular weightheparin to a final concentration of 0.2 U/mL. Platelets from bloodcollected with ACD were isolated by centrifugation and tagged with 0.5mCi/mL Na⁵¹Cr. Red blood cells were also isolated from the ACD wholeblood and washed. The Na⁵¹Cr tagged platelets and washed red blood cellswere combined with platelet poor plasma to give a final plateletconcentration of 250,000 platelets/μL and a 40% hematocrit. Finally,¹²⁵I-fibrinogen was added to the whole blood suspension such that itrepresented approximately 2% of the total amount of fibrinogen. Plateletadhesion was measured from flowing whole blood in a cone-and-platedevice which produces laminar flow and a uniform rate of shear. Coatedcoupons were placed in the wells of the cone-and-plate device with 1.2mL of the whole blood suspension containing Na⁵¹Cr platelets and theassay was conducted for 15 minutes. The coupons were then rinsed withfresh buffer and the radioactivity was measured with a γ counter andcorrelated to the number of adherent platelets (Na⁵¹Cr platelets) andadsorbed fibrinogen (¹²⁵I-fibrinogen) based on the radioactivity of theoriginal whole blood suspension. Compared to the uncoated stainlesssteel coupon, all coated coupons significantly reduced platelet adhesionand fibrinogen adsorption (FIG. 46).

Example 61: MEM Elution Assay—Cytotoxicity Assessment of Compounds 1-D,6-D, 8-D, 9-D, 15, and 16

Compounds 1-D, 6-D, 8-D, 9-D, 15, and 16 were weighed and incubated inMEM media at a 4 g: 20 mL ratio for 24 hours at 37° C. L-929 mousefibroblast cells were seeded and incubated at 37° C. in 5% CO₂ to obtainsub-confluent monolayers of cells. The growth medium in triplicatecultures was replaced with MEM extract (2 mL). Triplicate cultures werealso prepared as positive and negative controls. Cell cultures wereexamined under microscope after 24 hours to evaluate cellularcharacteristics and percent lysis. Under the conditions of this test,the MEM extracts showed no evidence of causing cell lysis or toxicity.The same experimental procedure was applied to all Compounds describedin Examples 1 to 16.

Example 62: Direct Contact Assay of Compounds 1-D, 6-D, 8-D, 9-D, 15,and 16

The viability of HeLa epithelial cells in direct contact with testmaterials was used to assess the potential cytotoxicity of Compounds1-D, 6-D, 8-D, 9-D, 15, and 16.

Samples of Compounds were solvent cast on agar-supported Supor filters.Subsequently, a monolayer of HeLa cells were cultured directly on thefilter, in the presence of MEM culture media. After 24 hours ofincubation, the Supor filter was rinsed and stained with succinicdehydrogenase. Viable cells were identified by a positive purple stainand cytotoxicity was determined by examining the stained filter for cellexclusion zones around the cast material, or a low cell density. Eachcytotoxicity assay included a positive and negative control. The sameexperimental method was applied to all Compounds described in Examples1-16.

Example 63: Partial Thromboplastin Assay of Compound 1-D

Compound 1-D was weighed and exposed to citrated human plasma at a ratioof 0.2 g test sample to 1 mL of plasma for 15 minutes at 37° C. At theend of incubation period, a PTT reagent of Rabbit Brain Cephalin (RBC)and an activator reagent (calcium chloride) were added to the plasmasamples. The plasma samples were then analyzed on the Cascade M-4 manualcoagulation analyzer for the time required to form a clot. By thisassay, Compound 1-D was considered to be a non-activator of theintrinsic pathway. The same experimental method was applied to allCompounds described in Examples 1-16.

Example 64: In Vivo Studies in Porcine Model

Stents of different types (bare metal, test Compound, and testCompound+1% PTX) were implanted in porcine coronary arteries (castratedmale farm porcines, Sus scrofa domestica; weight 40-50 kg at time ofstent implantation). Each animal received ASA (0.081 g) and Clopidogrel(0.075 g) by mouth daily for three days prior to stent implant, and werefasted overnight before the procedure. For surgical procedures, aftersedation a marginal ear vein was cannulated for infusion of intravenousfluids and medications. The animal was intubated for administration ofanesthetic gases and placed on the catheterization table. Under sterileconditions, a vascular introducer sheath was placed in the right femoralartery by surgical cut down. Continuous hemodynamic monitoring andelectrocardiographic monitoring was maintained throughout the procedure.Using the guide catheter as a calibration reference, the diameter of thevessel at reference sites proximal and distal to the intended site ofimplant, as well as the target site diameter, was measured. Stents wereimplanted in LAD, RCA and LCX arteries in each animal and were sized˜15% larger than the target site diameter by balloon catheter expansion.At termination seven days after stent implantation, the animals wereeuthanized, the heart was excised and examined for any abnormalities,and the vasculature was perfused with saline solution to clear theblood. Hearts were kept immersed in fresh formalin until excision ofstents for microscopic analysis (FIG. 47). At termination, the liver,spleen and kidneys from test animals were harvested for furtheranalysis. A careful analysis of multiple sections of these organsrevealed no remarkable pathological features. The tissue from all threeorgans showed normal architecture and did not exhibit any sign ofinflammation or tissue injury.

Example 65: Compound 3—Coating Quality, Stability and Integrity onStents

COATING QUALITY: Compound 3 (0.2 g) was dissolved in THF: toluene, wasstirred for 24 hours at room temperature, and the solution was sprayedonto stents using an EFD spray system using settings specific toCompound 3. The stents were dried in a 50° C. flow oven for 20-24 hours.The stent coating was assessed for uniform strut coverage by SEM. Stentswere then either crimped and deployed or kept as cut. After processing,the coatings on both stents and balloons were assessed by microplateanalysis (Ex 320 nm, Em 540 nm). Coating quantity was measured directlyon both the stent (as cut: 97.88, deployed: 54.39) and balloon (36.69),as well as after stripping with MeOH for 24 hours (stent as cut: 47.03,deployed: 29.79, balloon: 10.55). Transfer of Compound 3 to the balloonduring deployment was examined by UV light.

COATING STABILITY: Stents were coated with Compound 3 as above andstored in the dark at room temperature for 42 days. Stent coatings werestripped in MeOH and the coating was quantified using a microplatereader (Ex 320 nm, Em 540 nm) after 1 and 42 days in storage. Themicroplate readings were similar regardless of storage time ((1day)=40.85, (42 days)=39.80). SEM confirmed that the coating on thestent did not change after 42 days in storage (FIG. 48). Similarly,stents were coated with Compound 3 as above and were incubated inporcine blood (1.5 mL) at 37° C. on a shaker (60 rpm), with dailychanges of the blood. After 7 days stents were examined with SEM (FIG.49—right). Stents were also incubated in porcine blood (1.5 mL) at 4° C.for 24 hours with the blood changed after 4, 8 and 24 hours. SEM ofthese stents revealed a considerable amount of protein deposition, andminimal loss of coating (FIG. 49—left). The coating was also evaluatedusing microplate analysis (Ex: 320 nm, Em: 540 run): (0 hour)=77.18, (1hour)=71.43, (4 hours)=67.74, (24 hours)=37.16, (7 days)=24.64.

COATING INTEGRITY: Stents were coated with Compound 3 as above andcrimped on balloons. A female pig (20 lb) was implanted with a Compound3 coated stent in each of the following arteries: left anteriordescending artery (LAD), left circumflex artery (LCX), and rightcoronary artery (RCA). Stents were explanted 45-90 minutes afterimplantation (FIG. 50). LAD and LCX explanted stents were stripped inMeOH for coating quantification by microplate analysis (Ex: 320 nm, Em:540 nm): (LAD)=29.62, (LCX)=28.12.

OTHER EMBODIMENTS

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

What is claimed is:
 1. An implantable medical device having a surfaceand a matrix coating applied to said surface of said implantable medicaldevice, said matrix coating consisting of components having a molecularweight of less than 20 kDa, said matrix coating comprising (i) anoligomer and (ii) a biologically active agent, wherein said matrixcoating is self-eliminating or bioerodible upon implantation into asubject and wherein said biologically active agent when on theimplantable medical device resides solely within said matrix coating. 2.The implantable medical device of claim 1, wherein said surface is amaterial selected from metals, metal alloys, ceramics, base polymers,and glasses.
 3. The implantable medical device of claim 1, wherein saidmatrix and said biologically active agent are applied to said surface byspray coating, printing, or dip coating said implantable medical device.4. The implantable medical device of claim 1, wherein said biologicallyactive agent is selected from proteins, peptides, carbohydrates,antibiotics, antiproliferative agents, rapamycin macrolides, analgesics,anesthetics, antiangiogenic agents, antithrombotic agents, vasoactiveagents, anticoagulants, immunomodulators, cytotoxic agents, antiviralagents, antibodies, neurotransmitters, psychoactive drugs,oligonucleotides, vitamins, lipids, and prodrugs thereof.
 5. Theimplantable medical device of claim 1, wherein said oligomer comprises apolyurethane, polyurea, polyamides, polyalkylene oxide, polycarbonate,polyester, polylactone, polysilicone, polyethersulfone, polyolefin,polyvinyl, polypeptide, polysaccharide, or combinations thereof. 6-7.(canceled)
 8. The implantable medical device of claim 1, wherein saidoligomer is an oligofluorinated oligomer.
 9. An implantable medicaldevice having a surface and a matrix coating applied to said surface ofsaid implantable medical device, said matrix coating comprising anoligofluorinated oligomer, wherein said matrix coating isself-eliminating or bioerodible upon implantation into a subject andwherein said oligofluorinated oligomer when on the implantable medicaldevice resides solely within said matrix coating.
 10. (canceled)
 11. Theimplantable medical device of claim 8, wherein said oligofluorinatedoligomer is described by formula (II):F_(T)-[B-(Oligo)_(n)-B—(F_(T))_(g)  (II) wherein B comprises a urethane;oligo comprises polypropylene oxide, polyethylene oxide, polycarbonate,or polytetramethyleneoxide; F_(T) is an oligofhioro group; g is 0 or 1;and n is an integer from 1 to
 10. 12. The implantable medical device ofclaim 11, wherein F_(T) has the formula:CF₃(CF₂)_(p)X,(CF₃)₂CF(CF₂)_(P)X, or(CF₃)₃C(CF₂)_(p)X, wherein X isCH₂CH₂—, (CH₂CH₂O)_(n), CH₂CH(OH)CH₂O—, CH₂CH(CH₂OH)O—, or a bond; p isan integer between 2 and 20; and n is an integer between 1 and
 10. 13.The implantable medical device of claim 1, wherein said device isselected from cardiac-assist devices, catheters, stents, prostheticimplants, artificial sphincters, and drug delivery devices. 14.(canceled)
 15. The implantable medical device of claim 1, wherein saidbiologically active agent is uniformly distributed throughout saidmatrix coating.
 16. The implantable medical device of claim 15, whereinsaid biologically active agent is dissolved in said matrix coating. 17.The implantable medical device of claim 1, wherein said matrix coatinghas a thickness of 0.1 to 5 microns.
 18. (canceled)
 19. A method formaking a coated implantable medical device having a surface, said methodcomprising the step of coating said surface with a matrix coatingcomprising an oligofluorinated oligomer, wherein said matrix coating isself-eliminating or bioerodible upon implantation into a subject andwherein said oligofluorinated oligomer when on the implantable medicaldevice resides solely within said matrix coating, wherein said step ofcoating comprises dissolving the constituents of said matrix coating ina solvent to form a solution and applying said solution to the surfaceof said implantable medical device. 20-23. (canceled)
 24. The method ofclaim 19, wherein said implantable medical device is selected fromcardiac-assist devices, catheters, stents, prosthetic implants,artificial sphincters, and drug delivery devices.
 25. The method ofclaim 24, wherein said implantable medical device is a stent. 26.(canceled)
 27. (canceled)
 28. The method of claim 19, wherein said stepof coating comprises applying said matrix coating in a thickness of 0.1to 5 microns.
 29. The method of claim 19, wherein said uncoatedimplantable medical device is coated to produce a coated implantablemedical device, said coated implantable medical device having, uponimplantation into an animal, reduced protein deposition, reducedfibrinogene deposition, reduced platelet deposition, or reducedinflammatory cell adhesion in comparison to said uncoated implantablemedical device.
 30. A stent having a surface and a matrix coatingapplied to said surface of said stent, said matrix coating consisting ofcomponents having a molecular weight of less than 20 kDa, said matrixcoating comprising (i) an oligomer and (ii) a biologically active agentselected from antiproliferative agents and rapamycin macrolides, whereinsaid matrix coating is self-eliminating or bioerodible upon implantationinto a subject and wherein said biologically active agent when on thestent resides solely within said matrix coating. 31-36. (canceled)
 36. Amethod for delivering a biologically active agent to a subject, saidmethod comprising implanting into said subject an implantable medicaldevice of claim 1.